CA2215700A1 - Aromatic compounds useful as tachykinin antagonists - Google Patents
Aromatic compounds useful as tachykinin antagonists Download PDFInfo
- Publication number
- CA2215700A1 CA2215700A1 CA002215700A CA2215700A CA2215700A1 CA 2215700 A1 CA2215700 A1 CA 2215700A1 CA 002215700 A CA002215700 A CA 002215700A CA 2215700 A CA2215700 A CA 2215700A CA 2215700 A1 CA2215700 A1 CA 2215700A1
- Authority
- CA
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- Prior art keywords
- compound
- formula
- group
- 4alkyl
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- 102000003141 Tachykinin Human genes 0.000 title claims description 25
- 108060008037 tachykinin Proteins 0.000 title claims description 25
- 239000005557 antagonist Substances 0.000 title description 11
- 150000001491 aromatic compounds Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 139
- 239000001257 hydrogen Substances 0.000 claims abstract description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 49
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 29
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 27
- 208000002193 Pain Diseases 0.000 claims abstract description 22
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 21
- 206010047700 Vomiting Diseases 0.000 claims abstract description 16
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 15
- 150000002367 halogens Chemical class 0.000 claims abstract description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 15
- 208000019695 Migraine disease Diseases 0.000 claims abstract description 11
- 206010027599 migraine Diseases 0.000 claims abstract description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 241000689227 Cora <basidiomycete fungus> Species 0.000 claims abstract description 5
- 241000036848 Porzana carolina Species 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 229910052701 rubidium Inorganic materials 0.000 claims abstract description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 5
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 5
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims abstract description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims abstract description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 13
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract 13
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract 3
- 206010061218 Inflammation Diseases 0.000 claims abstract 3
- 230000004054 inflammatory process Effects 0.000 claims abstract 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 42
- -1 amino, methylamino, dimethylamino, diethylamino, azetidinyl Chemical group 0.000 claims description 39
- 239000000460 chlorine Chemical group 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 26
- 208000035475 disorder Diseases 0.000 claims description 24
- 150000002431 hydrogen Chemical group 0.000 claims description 19
- 239000000543 intermediate Substances 0.000 claims description 19
- 230000002265 prevention Effects 0.000 claims description 16
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 15
- 239000011737 fluorine Chemical group 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 11
- 125000006413 ring segment Chemical group 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
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- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000001359 1,2,3-triazol-4-yl group Chemical group [H]N1N=NC([*])=C1[H] 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 239000002243 precursor Substances 0.000 claims description 4
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
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- 206010036376 Postherpetic Neuralgia Diseases 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 150000001540 azides Chemical class 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- GRHBQAYDJPGGLF-UHFFFAOYSA-N isothiocyanic acid Chemical compound N=C=S GRHBQAYDJPGGLF-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 4
- 125000003363 1,3,5-triazinyl group Chemical class N1=C(N=CN=C1)* 0.000 claims 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- 150000003920 1,2,4-triazines Chemical class 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 201000010099 disease Diseases 0.000 description 19
- 102100024304 Protachykinin-1 Human genes 0.000 description 13
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- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 101800003906 Substance P Proteins 0.000 description 9
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000002512 chemotherapy Methods 0.000 description 6
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 6
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- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 5
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
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Abstract
The present invention relates to compounds of formula (I), wherein R1 and R4 represent hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C37cycloalkyl, C3-7cycloalkylC1-4alkyl, C1-6alkoxy, C1-4alkyl substituted by a hydroxy or C1-4alkoxy group, OCF3, hydroxy, trifluoromethyl, trimethylsilyl, nitro, CN, SRa, SORa, SO2Ra, CORa, CO2Ra or CONRaRb where Ra and Rb are each independently hydrogen or C1-4alkyl; R2, R3 and R5 represent hydrogen, halogen, C1/6alkyl, C1-6alkoxy substituted by a C1-4alkoxy group, or trifluoromethyl; R6, R7 and R8 each independently represent hydrogen or a C14alkyl group optionally substituted by a hydroxy group; and Het represents a 5 or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =O, =S or a C1-4alkyl group, and optionally substituted by a group of the formula ZNR9R10. The compounds are of particular use in the treatment of pain, inflammation, migraine and emesis.
Description
CA 0221~700 1997-09-17 AROMATIC COMPOUNDS USEFUL AS TACHYKININ ANTAGONISTS
This invention relates to a class of heteroaromatic compounds which s are useful as tachykinin antagonists.
The tachykinins are a group of naturally occurring peptides found widely distributed throughout m~mm~ n tissues, both within the central nervous system and in peripheral nervous and circulatory systems.
The tachykinins are distinguished by a conserved carboxyl-terminz~l o sequence: I
Phe-X-Gly-Leu-Met-NH2 At present, there are three known m~mm~ n tachykinins referred to as substance P, neurokinin A (NKA, substance K, neuromedin L) and neurokinin B (NKB, neuromedin K) (for review see J.E. Maggio, Peptides (1985) 6(suppl. 3), 237-242). The current nomenclature (le.cign~tes the three tachykinin receptors mediating the biological ~rtion~ of substance P, NKA and NKB as the NK1, NK2 and NK3 receptors, respectively.
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic infl ~mm ~tory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, ;nfl~mm~tory diseases of the gut including ulcerative colitis and Crohn's disease, ocular 2~ injury and ocular infl~mm~tory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyper-reflexia is reviewed in "Tachykinin Receptors and Tachykinin Receptor Antagonists", C.A. Maggi, R.
Pat~crl-ini, P. Rovero and A. Giachetti, J. Auto7z. Pharmacol. (1993) 13, 23-93.
CA 0221~700 1997-09-17 W 096/29317 2 PCT/GB~6/00586 For instance, substance P is believed inter alia to be involved in the neurotr~n.smi.s.sion of pain sensations [Otsuka et al, "l~ole of Substance P
as a Sensory 'rr~n.smitter in Spinal Cord and Sympathetic Ganglia" in 1982 Substance P i71 the Nervous System, Ciba Foundation Symposium 91, 13-34 (published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Act as a Pain Tr~n.smitter?" TIPS (1987) 8, 506-510], sperificc~lly in the tr~n.smi.s.qion of pain in migraine (E,.E.B. Sandberg et al, J. Med Chem, (1982) 25, 1009) and in arthritis [Levine et al Science (1984) 226, 547-549]. Tachykinins have also been implicated in gastrointestinal 0 (GI) disorders and diseases of the GI tract such as infl~mm~tory bowel disease [Mantyh et al Neuroscience (1988) 25(3), 817-37 and D. Regoli in "Trends in Cluster Headache" Ed. Sicuteri et al Elsevier Scientific Publishers, Amsterdam (1987) page 85)] and emesis [F. D. Tatter.s~ll et al, Eur. J. Pharmacol., (1993) 250, R5-R6]. It is also h.ypothesised that there is a neurogenic merh~ni.sm for arthritis in which substance P may play a role [Kidd et al "A Neurogenic Merh~ni.sm for Symmetrical Arthritis" in The Lancet, 11 November 1989 and Gronblad et al, "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J.
Rheumatol. (1988) 15(12), 1807-10]. Therefore, substance P is believed to be involved in the infl~mm~tory response in diseases such as rheumatoid arthritis and osteoarthritis, and fibrositis [O'Byrne et al, Arthritis and Rheumatism (1990) ~, 1023-8]. Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions [Hamelet et al, Ca71. J. Pharmacol. Physiol. (1988) 66, 1361-7], immunoregulation [Lotz et al, Science (1988) 241, 1218-21 and ~imball et al, J. Immunol. (1988) 141(10), 3564-9] vasodilation, bronchospasm, reflex or neuronal control of 7 the viscera p~antyh et al, PNAS (1988) 85, 3235-9] and, possibly by arresting or slowing ~-amyloid-mediated neurodegenerahve changes [Yankner et alJ Science (1990) 250, 279-82] in senile dementia of the Alzheimer type, Alzheimer's disease and Down's Syndrome.
CA 0221~700 1997-09-17 Tachykinin antagonists may also be useful in the treatment of small cell carcinomas, in particular small cell lung cancer (SCLC) Langdon et al, Cancer Research (1992) 52, 4~54-7].
Substance P may also play a role in demyelinating diseases such as s multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et al, poster C.I.N.P. XVlIIth Congress, 28th June-2nd July 1992], and in disorders of blz3~ r filnction such as bladder detrusor hyper-r-?flç~i~
(Lancet, 16th May 1992, 1239).
It has furthermore been suggested that tachykinins have utility in 0 the following disorders: depr~ ior-, dysthymic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as ~ngin?~ and Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fasri~ i.c, reflex sympathetic dystrophy such as shoulder/hand syndrome, a~lrliction 5 disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorders related to immune çnll~nc~ment or suppression such as systemic lupus erythmatosus (European patent specification no. 0 436 334), ophtl~lmic disease such as conjuctivitis, vernal conjunctivitis, and the like, and cutaneous diseases such as contact dermatitis, atopic 20 dermatitis, urtic~ri~, and other eczematoid dermatitis (European patent specification no. 0 394 989).
European patent spe-ifir~tion no. O B77 394 (published 5th January 1994) discloses morpholine and thiomorpholine tachykinin receptor antagonists of the general formula R3~ X ~ R
R2~ J~ N J' R
R
wherein Rln is a large variety of substituents;
R2U and R3~ are inter alia hydrogen;
R4" is inter alia CA 0221~700 1997~09~17 ~R~-R5a is inter alia optionally substituted phenyl;
R6a, R7a and R3a are a variety of substituents;
XaisO,S,SOorSO2;
yaiS inter alia O; and ZaiS hydrogen or Cl 4alkyl.
We have now found a further class of non-peptides which are potent antagonists of tachykinins, especially of substance P.
The present invention provides compounds of the formula a):
Het N~ ~R2 OMe (I) wherein Rl represents hydrogen, halogen, Cl.6alkyl2 C2.6alkenyl, C2.6alkynyl, 15 C3.7cycloalkyl, C3.7cycloalkylCl-4alkyl, Cl.6alkoxy, Cl.~alkyl substituted by a hydroxy or Cl.4alkoxy group, OCF3, hydroxy, tri~luoromethyl, trimethylsilyl, nitro, CN, SRa, SORa, SO2RQ, CORa, CO2Ra or CONRaRb where Ra and Rb are each independently hydrogen or Cl.4alkyl;
R2 and R3 each independently represent hydrogen, halogen, 20 Cl.6alkyl, Cl.6alkoxy substituted by a Cl.4alkoxy group, or trifluoromethyl;
CA 0221~700 1997-09-17 R4 represents hydrogen, halogen, C1 6alkyl, C2.6alkenyl, C2.6aIkynyl, C3.7cycloalkyl, C3.7cycloalkylC1.4alkyl, C1.6alkoxy, C1.4alkyl substituted by a hydroxy or C1.4alkoxy group, OCF3, hydroxy, trifluoromethyl, trimethylsilyl, nitro, CN, SRs, SORA, SO2RA, CORA, CO2Ra, CONRsRb where RA and Rb are as previously defined;
R5 represents hydrogen, halogen, C1.6alkyl, C1.6alkoxy substituted by a C1.4alkoxy group, or trifluoromethyl;
R6, R7 and R3 each independently represent hydrogen or a Cl.4alkyl group optionally substituted by a hydroxy group;
Het represents a 5- or 6-membered heterocyclic ring cont~ining 2 or 3 nitrogen atoms optionally substituted by =O, =S or a Cl.4~1kyl group, and optionally substituted by a group of the formula ZNR9Rl0 where Z is C1.6alkylene or C3.6cycloalkyl;
R9 is hydrogen or C,.4alkyl, C3.7cycloalkyl, C3.7cycloalkylC1.4alkyl, or C2.4alkyl substituted by C1.~alkoxy or hydroxyl;
R10 is hydrogen or C1.4alkyl, C3.7cycloalkyl, C3.7cycloalkylC1.4alkyl, or C2.4alkyl substituted by C1 1~lko~y, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R9, R10 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy or Cl.4alkoxy optionally substituted by a Cl.4alkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH
or NRC moiety where Rc is Cl.4alkyl optionally substituted by hydroxy or Cl.4alkoxy;
or R9, R10 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
CA 022l~700 l997-09-l7 W 096/29317 ~ PCT/GB96/00586 or Z, R9 and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which may optionally cont~in an oxygen ring atom;
and pl~rm~ceutically acceptable salts thereof.
Certain particularly apt compounds of the present invention include those wherein Rl is hydrogen, Cl 4alkyl, Cl.4alkoxy, h~logen or CF3.
Most aptly R2 is hydrogen, Cl.4alkyl, Cl ,alkoxy, halogen or CF3.
Most aptly R3 is hydrogen, fluorine, chlorine or CF3.
Favourably Rl is fluorine, (~hlf)rine or CF3.
o Favourably R2 is hydrogen, fluorine, chlorine or CF3.
Favourably R3 is hydrogen, fluorine, chlorine or CF3.
Preferably Rl and R2 are in the 3 and 5 positions of the phenyl ring.
More preferably, Rl is 3-fluoro or 3-CF3.
More preferably, R2 is 5-fluoro or 5-CF3.
More preferably, R3 is hydrogen.
Most preferably, Rl is 3-F or 3-CF3, R2 is 5-F or 5-CF3 and R3 is hydrogen.
Most aptly R4 is hydrogen.
Most aptly R5 is hydrogen, fluorine, chlorine or CF3.
Preferably R4 is hydrogen and R5 is hydrogen or 4-fluoro.
Most aptly R6 and R7 are each independently hydrogen or methyl.
Preferably R6 is hydrogen. Preferably R~ is hydrogen. Most preferably R3 and R7 are both hydrogen.
Most aptly R3 may be hydrogen or Cl.2alkyl optionally substituted by a hydroxy group. In particular, R3 may be hydrogen, methyl or hydroxymethyl.
Favourably Het is a 5-membered ring.
In particular, Het may represent a heterocyclic ring selected from:
-<\ ~ ; <\ ~ ; N~ ~ ;
N N N
z NR9Rl O
N ZNR R ~ ; and <
Particularly preferred heterocyclic rings represented by R6 are selected from:
H H H
N ~ N ~ ~ N ~
H H_N N ZNR9Rl0 H ~ ,N ~ ; and <
N ZNR R N ZNR R N
z NR9Rl O
Most especially, Het may represent a heterocyclic ring selected from:
H H
<~ ~ ; O ~ ~ ,N ~
N ZNR R N ZNR9Rl0 N ZNR R
A particularly preferred heterocyclic ring represented by Hetis:
CA 0221~700 1997-09-17 W 096/29317 8 PCT/GB~C/C~'8 N
HN~ ~
N ZNR9Rl0 With respect to compounds of the formula a), Z may be a linear, branched or cyclic group. Favourably Z contains 1 to 4 carbon atoms and 5 most favourably 1 or 2 carbon atoms. A particularly favourable group Z is CH2 .,.
With respect to compounds of the formula (I), R9 may aptly be a Cl-4alkyl group or a C2.4alkyl group substituted by a hydroxyl or Cl.2alkoxy group, Rl~ may aptly be a Cl 4alkyl group or a Cl.4alkyl group substituted o by a hydroxyl or Cl 2alkoxy group, or R9 and Rl~ may be linked so that, together with the nitrogen atom to which they are attached, they form an azetidinyl, pyrrolidinyl, piperidyl, morpholino, thiomorpholino, piperazino or piperazino group substituted on the nitrogen atom by a Cl.4alkyl group or a C2.4alkyl group substituted by a hydroxy or Cl.2alkoxy group.
Where the group NR9Rl0 represents a heteroaliphatic ring of 4 to 7 ring atoms and said ring cont~inq a double bond, a particularly preferred group is 3-pyrroline.
Where the group NR9Rl0 represents a non-aromatic azabicyclic ring system, such a system may contain between 6 and 12, and preferably 20 between 7 and 10, ring atoms. S~ hl~ rings include 5-azabicyclo[2. 1. l]hexyl, 5-azabicyclo[2.2. l]heptyl, 6-azabicyclo[3.2. l]octyl, 2-azabicyclo[2.2.2]octyl, 6-azabicyclot3.2.2]nonyl, 6-azabicyclo[3.3.1]nonyl, 6-azabicyclo[3 .2 .2] decyl, 7-azabicyclo[4.3 .1] decyl, 7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially 2~ 5-azabicyclo[2.2.1]heptyl and 6-azabicyclo[3.2.1]octyl.
Where Rl~ represents a C2 4alkyl group substituted by a 5 or 6 membered heteroaliphatic ring cont~ining one or two heteroatoms selected from N, O and S, suitable rings include pyrrolitlino, pipçri-lino, piperazino, morpholino, or thiomorpholino. Particularly plef~rled are nitrogen CA 0221~700 1997-09-17 cont~inin~ heteroaliphatic rings, especially pyrrolidino and morpholino r~gs.
Particularly suitable moieties ZNR9Rl0 include those wherein Z is CH2 or CH2CH2 and NR9R'0 is amino, methylamino, dimethylamino, s diethylamino, azetidinyl, pyrrolidino and morpholino.
Further preferred moieties represented by ZNR9Rl0 are those wherein Z is CH2 or CH2CH2, R9 represents hydrogen, Cl.4~1kyl or C3.6cycloalkyl and Rl~ is C2.4alkyl substituted by one or two substituents selected from hydroxy, Cl.2alkoxy, azetidinyl, pyrrolidino, piperidino, 0 morpholino or thiomorpholino.
In particular, Z is preferably CH2 and NR9Rl0 is preferably dimethylamino, azetidinyl or pyrrolidino, especially dimethyl~mino.
As used herein, the term "alkyl" or "alkoxy" as a group or part of a group means that the group is straight or branched. F.x~mples of suitable ~lkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. F,x~mples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
The cycloalkyl groups ~ efer- ed to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A sllit~hle cycloalkylalkyl group may be, for example, cyclopropylmethyl.
As used herein, the terms "~lkenyl" and "alkynyl" as a group or part of a group means that the group is straight or branched. Examples Gf suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is propargyl.
When used herein the term halogen means fluorine, chlorine, bromine and iodine. The most apt halogens are fluorine and ~hlorine of which fluorine is preferred.
One favoured group of compounds of the present invention are of the formula (Ia):
CA 0221~700 1997-09-17 ~ A
"'" N O ~ A
OMe (Ia) wherein R8 and Het are as defined in relation=to formula a) and Al is fluorine or CF3;
A2 is fluorine or CF3; and A3 is hydrogen or fluorine;
and ph~rm~ceutically acceptable salts thereo~
Specific compounds within the scope of this invention include:
4-(N-((2-((3,5-bis(trifluoromethyVphenyvmethyloxy)- l-(S)-phenyl)ethyl-N-10 (2'-methoxyethyl))aminomethyV-5-(N',N'-dimethylaminomethyV-1,2,3-triazole;
and pharmaceutically acceptable salts thereof.
In a further aspect of the present invention, the compounds of formula a) will preferably be prepared in the form of a ph~rm~eutically 15 acceptable salt, especially an acid addition salt.
For use in medicine, the salts of the compounds of formula a) wi~l be non-toxic pl~rm~ceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. S~ hle 20 ph~rm~ceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mi~ing a solution of the compound according to the invention with a solution of a p~rm~( eutically acceptable acid such as hydrochloric acid, filmz~ric acid, p-toluenesulphonic acid, maleic acid, suc(~inic acid, acetic acid, citric acid, CA 0221~700 1997-09-17 tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of s the invention carry an acidic moiety, suitable ph~rm~reutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g.
sodium or potassium salts; and ~lk~line earth metal salts, e.g. calcium or magnesium salts.
The salts may be formed by conventional means, such as by reacting lO the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed i71 uacuo or by freeze drying or by ~x~ nging the anions of an existing salt for another anion on a suitable ion exchange resin.
The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula a) which are readily convertible in vivo into the required compound of formula (I).
Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
A prodrug may be a pl~rm~ologically inactive derivative of a biologically active substance (the "parent drug" or "parent molecule") that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible function~lity.
The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.
CA 022l~700 l997-09-l7 The compounds according to the invention have at least three asymmetric centres, and may accordingly exist botll as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present 5 invention.
The preferred compounds of the formula (I) will have the pleLerled stereochemistry as shown in formula (Ib) ~S Rl R6 ~ ~ R
OMe (Ib) The present invention further provides ph~rm~ceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable callier or excipient.
Preferably the compositions according to the invention are in unit 15 dosage forms such as tablets, pills, capsules, powde~rs, granules, solutions or susp~n~ion~, or suppositories, for oral, parenter~l or rectal a-lmini.ctration, or a~lmini~tration by inh~l~tion or insufflation.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a ph~rm~ceutical carrier, e.g. conventional 20 tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, ~icalcium phosphate or gums, and other ph~rm~ceutical diluents, e.g. water, to form a solid preformulation composition cont~ining a homogeneous mixture of a compound of the present invention, or a non-toxic ph~rm~eutically acceptable salt thereo~
CA 0221~700 1997-09-17 When r~ferring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
This solid preformulation composition is then subdivided into unit dosage forms of the type described above cont~ining from 0.1 to about ~00 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, 0 the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
The two components can be separated by an enteric layer which serves to resist disintegration in the stom~(~h and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and ce~lulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for a-lmini.stration orally or by injection 20 include aqueous solutions, suitably flavoured syrups, aqueous or oil suspen.sion.s, and flavoured emlll.sion.s with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and .simil~r ph:~rm~ceutical vehicles. Sllit~hle. dispersing or suspending agents for aqueous susp~n.sions include synthetic and natural gums such as tragacanth, ~c~ l gin ~te, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Preferred compositions for a-lmini.stration by injection include those comprising a compound of formula a), as the active ingredient, in association with a surface-active agent (or wetting agent or sllrf~ct~nt) or 30 in the form of an emulsion (as a water-in-oil or oil-in-water emulsion).
CA 0221~700 1997-09-17 Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. TweenTM 20, 40, ~;0, 80 or 85) and other sorbitans (e.g. SpanTM 20, 40, 60, 80 or 86). Compocition.~
with a surface-active agent will conveniently comprise between 0.06 and 5% surface-active agent, and preferably between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example m~nnitol or other pharmaceutically acceptable v~hirle.~, if necessary.
Sl-it~hle emulsions may be prepared using commercially av~ hle fat emulsions, such as Intralipid , Liposyn , InfonutrolTM, LipofundinTM
o and LipiphysanTM. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g.
egg phospholipids, soybean phospholipids or soybean, lecithin) and water.
It will be appreciated that other ingredients may be added, for example gylcerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion will preferably comprise fat droplets between 0.1 and l.O~lm, particularly 0.1 and 0.5,um, and have a pH in the range of 5.5 to 8Ø
Particularly preferred emulsion compositions are those prepared by mixing a compound of formula a) with IntralipidTM or the components thereof (soybean oil, egg phospholipids, glycerol and water).
Compositions for inh~l~tion or insu~lation include solutions and suspen.~i-ns in ph~rm~eutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compo.ci~ion.s may contain suitable pharmaceutically acceptable excipients as set out above.
Preferably the compositions are a-lmini~tered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably 30 sterile ph~rm~eutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the CA 0221~700 1997-09-17 nebulising device or the nebllli.qing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be a.iminiqtered, preferably orally or nasally, from devices which deliver the formulation in an appropriate s manner.
The present invention futher provides a process for the preparation of a p~rm~(~eutical composition comprising a compound of formula a), which process comprises bringing a compound of formula a) into association with a pharmaceutically acceptable carrier or excipient.
o The compounds of formula a) are of value in the treatment of a wide variety of rlini~l conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity.
Thus, for example, an excess of tachykinin, and in particular substance P, activity is implicated in a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific ~nim~l phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-trallm~tic stress disorder and acute stress disorder, and generalised anxiety disorders; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallucinations; delerium, dementia, and ~ amnestic and other cognitive or neurodegenerative disorders, such as Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, vascular dementia, and other dementias, for example, due to HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, CA 0221~700 1997-09-17 W 096/29317 1~ - PCT/GB96/00~86 Creutzfeldt-Jakob disease, or due to multiple aetiologies; Parkinson's disease and other extra-pyr~mi~l~l movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced parkinsonism, neuroleptic m~ n~nt syndrome, neuroleptic-induced acute s dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremour; substance-related disorders ~ricing from the use of alcohol, amphetamines (or amphet~mine-like substances) caffeine, c~nn~hi.~, cocaine, hallucinogens, inh~l~nts and aerosol propellants, nicotine, opioids, phenylglycidine derivatives, o sedatives, hypnotics, and anxiolytics, which substance-related disorders include dependence and abuse, intoxication, withdrawal, intoxication delerium, withdrawal delerium, persisting dementia, psychotic disorders, mood disorders, anxiety disorders, sexual dysfunction and sleep disorders;
epilepsy; Down's syndrome; demyelinating diseases such as MS and ALS
5 and other neuropathological disorders such as peripheral neuropathy, for example diabetic and chemotherapy-induced neuropathy, and postherpetic neuralgia, trig~min~l neuralgia, segmental or intercostal neuralgia and other neuralgias; and cerebral vascular disorders due to acute or chronic cerebrovascular damage such as cerebral infarction, subarachnoid 20 haemorrhage or cerebral oedema.
Tachykinin, and in particular substance P, activity is also involved in nociception and pain. The compounds of the present invention will therefore be of use in the prevention or treatment of diseases and conditions in which pain pre(lomin~tes, including soft tissue and 2s peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, episiotomy pain, and burns; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for 30 example, dysmenorrhoea, and labour pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for CA 0221~700 1997-09-17 example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, tic douloureux, atypical facial pain, nerve root damage, and arachnoiditis; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage; low back pain; sciatica; ankylosing spondylitis, gout; and scar pain.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive o airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm;
infl:~mm~tory diseases such as infl~mmatory bowel disease, psori~ci~
fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn;
allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; opht}~lmiG conditions associated with cell proliferation such as proliferative vitreoretinopathy; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of neoplasms, including breast tumours, neuroganglioblastomas and small cell carcinomas such as small cell lung cancer.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of gastrointestinal (GI) disorders, including infl~mm~tory disorders and diseases of the GI tract such as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disorders associated with the neuronal control of viscera, ulcerative colitis, (~rohn's disease, irritable bowel syndrome and emesis, including acute, delayed or anticipatory emesis such as emesis induced by chemotherapy, ra~ tion, toxins, viral or bacterial infections, pregn~ncy, vestibular disorders, for CA 0221~700 1997-09-17 example, motion sickness, vertigo, dizziness and Meniere's disease, ~ul ~e. ~, migraine, variations in intercranial pressure, gastro-oesophageal reflux disease, acid indigestion, over indulgence in food or drink, acid stomach, waterbrash or regurgitation, heartburn, for example, episodic, nocturnal or meal-induced heartburn, and dyspepsia.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of a variety of other conditions including stress related somatic disorders; reflex sympathetic dystrophy such as shoulderlhand syndrome; adverse immunological reactions such as o rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosus;
plasma extravasation resulting from cytokine chemotherapy, disorders of bladder function such as cystitis, bladder detrusor hyper-reflexia and incontinence; fibrosing and collagen diseases such as scleroderma and 1S eosinophilic fasl~ioli~sis; disorders of blood ~low caused by vasodilation and vasospastic diseases such as ~n~ina, vascular headache, migraine and Reynaud's disease; and pain or nociception attributable to or associated with any of the foregoing conditions, especially the tr~n.smi.s.sion of pain in migraine.
The compounds of formula a) are also of value in the treatment of a combination of the above conditions, in particular in the treatment of comhined post-operative pain and post-operative nausea and vl miting The compounds of formula (I) are particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. Most especially, the compounds of formula ~[) are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents including those routinely used in cancer chemotherapy.
F',~mples of such chemotherapeutic agents include alkylating agents, for example, nitrogen mustards, ethyleneimine compounds, alkyl CA 0221~700 1997-09-17 sulphonates and other compounds with an alkylating action such as nitrosoureas, cisplatin and dacarbazine; antimetabolites, for example, folic acid, purine or pyrimidine antagonists; mitotic inhibitors, for example, vinca ~lk~loids and derivatives of podophyllotoxin; and cytotoxic s antibiotics.
Particular examples of chemotherapeutic agents are described, for instance, by D. J. Stewart in Nausea and Vomiti7~g: Recent Research and Clinical Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton, Florida, USA (1991) pages 177-203, especially page 188. Commonly used 0 chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil [R. J. Gralla et al in Cancer Treatme7lt Reports (1984) 68(1), 1~3-172].
The compounds of formula a) are also of use in the treatment of emesis induced by radiation including radiation therapy such as in the treatment of cancer, or radiation sickness; and in the treatment of post-operative nausea and vomiting.
It will be appreciated that the compounds of formula (I) may bepresented together with another therapeutic agent as a combined preparation for simultaneous, separate or sequential use for the relief of emesis. Such combined preparations may be, for example, in the form of a twin pack.
A further aspect of the present invention comprises the compounds of formula O in combination with a 5-HT3 antagonist, such as ondansetron, granisetron or tropisetron, or other anti-emetic medicaments, for example, a dopamine antagonist such as 30 metoclopramide. Additionally, a compound of formula (I) may be a-lmini.~tered in combination with an anti-infl~mmatory corticosteroid, CA 0221~700 1997-09-17 W Og6/29317 20 PCT/GB96/00586 such as dexamethasone. Furthermore, a compound of formula a) may be a-lmini.~tered in combination with a chemotherapeutic agent such as an aLkylating agent, antimetabolite, mitotic inhibitor or cytotoxic antibiotic, as described above. In general, the currently av~ hle. dosage forms of the s known therapeutic agents for use in such combinations will be suitable.
When tested in the ferret model of cisplatin-induced emesis (le.~r.rihed by F. D. Tattersall et al, in Eur. J. pharmacol., (1993) 250, R5-R6, the compounds of the present invention were found to attenuate the retching and vomiting induced by cisplatin.
o The compounds of formula (I~ are also particularly useful in the treatment of pain or nociception and/or infl~mm~tion and disorders associated therewith such as, for example, neuropathy, such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis and headache, 1S including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and m~ ry sinus pain,.
The present invention further provides a compound of formula (I) for use in therapy.
According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P.
The present invention also provides a method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises a~mini.~tration to a patient in need thereof of a tachykinin reducing amount of a compound of formula (I) or a composition comprising a compound of formula (I).
For the treatment of certain conditions it may be desirable to employ a compound according to the present invention in conjunction with another ph~rm~ologically active agent. For example, for the treatment of CA 0221=,700 1997-09-17 respiratory diseases such as asthma, a compound of formula a) may be used in conjllnct;on with a bronchodilator, such as a ~,2-adrenergic receptor antagonist or tachykinin antagonist which acts at NK-2 receptors. The compound of formula a) and the bronchodilator may be 5 a-lmini.qtered to a patient simultaneously, sequentially or in combination.
Likewise, a compound of the present invention may be employed with a leukotriene antagonists, such as a leukotriene D4 antagonist such as a compound selected from those disclosed in European patent specification nos. 0 480 717 and 0 604 114 and in US patent nos. 4,859,692 lo and 5,270,324. This combination is particularly useful in the treatment of respiratory diseases such as asthma, chronic bron~ itis and cough.
The present invention accordingly provides a method for the treatment of a respiratory disease, such as asthma, which method comprises a-lmini.stration to a patient in need thereof of an effective amount of a compound of formula a) and an effective amount of a bronchodilator.
The present invention also provides a composition comprising a compound of formula a), a bronchodilator, and a ph~rm~ceutically acceptable carrier.
It will be appreciated that for the treatment or prevention of migraine, a compound of the present invention may be used in conjunction with other anti-migraine agents, such as ergotamines or 5-HTl agonists, especially sumatriptan.
Likewise, for the treatment of behavioural hyperalgesia, a 2~i compound of the present invention may be used in conjunction with an antagonist of N-methyl D-aspartate (NMDA), such as dizocilpine.
For the treatment or prevention of infl~mm~tory conditions in the lower urinary tract, especially cystitis, a compound of the present invention may be used in conjunction with an anti-infl ~mm ~tory agent such as a bradykinin receptor antagonist.
The present invention also provides a composition comprising a compound of formula a), a bronchodilator, and a ph ~rm ~ceutically acceptable C~r~ r.
It will be appreciated that for the treatment or prevention of pain or nociception, a compound of the present invention may be used in conjunction with other analgesics, such as acetaminophen (paracetamol), aspirin and other NSAIDs and, in particular, opioid analgesics, especially morphine. Specific anti-infl~mm~tory agents include diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, piroxicam and sulindac.
o Suitable opioid analgesics of use in conjunction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydLromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereo~ Preferred salts of these opioid analgesics include morphine sulphate, morphine hydrochloride, morphine tartrate, codeine phosphate, codeine sulphate, dihydrocodeine bitartrate, diacetylmorphine hydrochloride, hydrocodone bitartrate, hydromorphone hydrochloride, levorphanol tartrate, oxymorphone hydrochloIide, alfentanil hydrochloride, buprenorphine hydrochloride, butorphanol tartrate, fentanyl citrate, meperidine hydrochloride, methadone hydrochloride, nalbuphine hydrochioride, propoxyphene hydrochloride, propoxyphene napsylate (2-naphthalenesulphonic acid (l: l) monohydrate), and pentazocine hydrochloride.
Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and CA 0221~700 1997-09-17 an analgesic as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of pain or nociception.
The excellent pharmacological profile of the compounds of the present invention offers the opportunity for their use in therapy at low doses thereby minimi.~ing the risk of unwanted side effects.
In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day.
o For example, in the treatment of conditions involving the neurotr~n~miq.cion of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be arlmini~tered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of emesis using an injectable formulation, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 1 mg/kg per day. The compounds may be a-lmini.~tered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be appreciated that the amount of a compound of formula (V
required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of a(lmini~tration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.
According to a general process (A), the compounds according to the invention may be prepared from compounds of formula (IV
CA 022l5700 l997-09-l7 OMe (II) wherein Rl, R2, R3, R4, R5, RG, R7 and R3 are as defined in relation to formula a) by reaction with a compound of formula (IIV:
LG-CH2-Het' (III) where Het' is a group of the formula Het as defined in relation to formula 0 (I) or a precursor therefor and LG is a leaving group such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g.
bromine, chlorine or iodine); and, if Het' is a precursor group, converting it to a group Het (in which process any reactive group may be protected and thereafter deprotected if desired).
This reaction may be performed in conventional manner, for example in an organic solvent such as dimethylform~mide in the presence of an acid acceptor such as potassium carbonate.
Thus, for instance, compounds in which Het is a 2-oxo- 1,3-imidazolyl, 1,3-imidazolyl or 1,2,3-triazolyl group, each of which is 20 substituted by ZNR9Rl0, may be prepared by the reaction of a compound of formula (II) with a compound of formula aV) CA 0221~700 1997~09~17 W 096/29317 -25 ~ PCT/GB96/00~86 LG LG LG
(CH~)n H (CH2)~ H (c) HN~ ~
LG LG LG
(IV) where n is an integer from 1 to ~, and each LG independently represents a leaving group as previously defined, followed by reaction of the resultant s compound with an amine of formula NHR9Rl0 to complete the group ZNRsRlo It will be appreciated that, where necessary, reactive groups may be protected, thus for example, the NH groups of an imidazolone of formula (IVa) may be protected by any suitable amine protecting group such as an lo acetyl group .
According to another process (B), compounds of formula (I) wherein Het represents 1,2,3-triazol-4-yl substituted by CH2NR9Rl~, may be prepared by reaction of a compound of formula (V) R ~ R Rl ~R9RI0 R ~ ~R2 OMe (V) 1~
with an azide, for example, sodium azide in a suitable solvent such as dimethylsulphoxide at a temperature of between 40~C and 100~C, followed CA 0221~700 1997-09-17 W 096/29317 2~ PCT/G~G/o~r86 by reduction of the carbonyl group adjacent to -NR9Rl0 using a suit~hle reducing agent such as lithium aluminium hydride at at a temperature between -10~C and room temperature, conveniently at room temperature.
Alternatively, according to a process (C), compounds of formula ~
wherein Het represents 1,2,3-triazol-4-yl substituted by CH2NR9Rl~, may be prepared by reaction of a compound of formula (Vl) ~0 OMe (VI) o with an amine of formula NHR9Rl0, in a suitable solvent such as an ether, for example, dioxan, at elevated temperature, for example, between 50~C
and 100~C, in a sealed tube, or the like. This reaction is based upon that described in Chem ische Berichte (1989) 122, p . 1963 .
According to another process, (D), compounds of formula (I) wherein 15 Het represents substituted or unsubstituted 1,3,5-tti~7.ine may be prepared by reaction of intermediates of formula (VII):
R5 Rl N ~ ~ R3R2 NH2 ~ R R
OMe (VII) with substituted or unsubstituted 1,3,5-t.ri~7.ine.
The reaction is conveniently effected in a suitable organic solvent, 5 such as acetonitrile, at elevated temperature, such as 80-90~C, preferably about 82~C.
According to a further process, (E), compounds of formula (V
wherein Het represents substituted or unsubstituted 1,2,4-t.ri~7.ine may be prepared by reaction of an intermediate of formula (VIIV with a 0 dicarbonyl compound of formula (IX):
~7 ~RRZ R,sJb,H
H2NHN 6)~ R R o OMe (VIII) (IX) wherein R35 represents H or a suitable substituent such as ZNR9Rl0.
lS The reaction is conveniently effected in a suitable organic solvent, such as an ether, e.g. tetrahydrofuran, conveniently at ~mbient temperature.
CA 0221~700 1997-09-17 According to a further process a~), compounds of formula wherein Het represents a substituted 1,2,4-triazolyl group may be prepared by reaction of an intermediate of formula aI) with a compound of formula (X) J~NHI~ Hal (X) wherein Hal is a halogen atom, for example, bromine, ~hlorine or io-line and Rl8 is H, CONH2 or OCH3 (which is converted to an oxo substituent under the reaction conditions), in the presence of a base, followed where necessary by conversion to a compound of formula a), for example, by 0 reduction of the CONH2 group to CH2NH2.
Suitable bases of use in the reaction include alkali metal carbonates such as, for example, potassium carbonate. The reaction is conveniently effected in an anhydrous organic solvent such as, for example, anhydrous dimethylformamide, preferably at elevated temperature, such as about 140~C.
A suitable reducing agent for the group CONH,;, is lithium aluminium hydride, used at between -10~C and room temperature.
According to another process, (G), compounds of formula a) wherein Het represents thioxotriazolyl may be prepared from intermediates of 20 formula (XI) CA 0221~700 1997-09-17 R Rl -R
~ N ~ ~ R3 H2NHN R6 ~ R R
OMe (XI) by reaction with a compound of formula HNCS, in the presence of a base.
Suitable bases of use in the reaction include organic bases such as, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene a)BU). The reaction is 5 conveniently effected in a suitable organic solvent, such as alcohol, e.g.
butanol.
Further details of suitable procedures will be found in the accompanying Fx~mples.
Intermediates of formula (V) may be prepared from intermediates of 0 formula aI) by reaction with an acetylene compound of formula HC_C~-CH2-Hal in the presence of a base such as potassium carbonate in a suitable solvent such as dimethylform~mide, conveniently at room temperature, followed by reaction of the resultant acetylene intermediate with an amide of formula Hal-CO-NR9Rl0 in the presence of suitable 15 catalysts including bis(triphenylphosphine) palladiumaI) chloride, coppera) iodide and triphenylphosphine in a suitable solvent such as triethylamine, preferably at reflux.
Intermediates of formula (VI) may be prepared from a compound of formula (XII) CA 0221~700 1997-09-17 ~R6 Hal OMe (XII) wherein Hal is a halogen atom, for example, rhlorine, bromine or iodine, especially rhlorine, by reaction with an azide, for example, sodium azide in a sllit~hle solvent such as dimethylsulphoxide at or below room 5 temperature.
Compounds of formula (XII) may be prepared by a dropwise addition of an intermediate of formula aI) to a dihaloacetylene of formula Hal-CH2-C_C-CH2-Hal where each Hal is independently chlorine, bromine or io(line, especially rhlorine. The reaction is conveniently effected in a suitable solvent such as dimethylform~mide in the presence of a base such as potassium carbonate.
Intermediates of formula (VII) may be prepared from intermediates of formula aI) by reaction with a compound of formula Hal-CH2-C(NH)NH2, where Hal is as previously defined.
1~ Intermediates of formula (VIII) may be prepared from intermediates of formula aI) by reaction with a compound of formula Hal-CH2-C(NH)NHNH-Boc, wherein Hal is as previously defined and Boc stands for t-butoxycarbonyl, followed by deprotection under acidic conditions.
Compounds of formula ax) are commercially available or may be prepared from commercially av~ hle compounds by known methods.
Compounds of formula (X) may be prepared as described in J. Med. Chem., (1984) 27, 849.
CA 0221~700 1997-09-17 Intermediates of formula (XI) may be prepared from the corresponding ester by treatment with hydrazine. The reaction is conveniently effected in a suitable organic solvent, such as an alcohol, for example, ethanol, at elevated temerpature.
s For compounds wherein Het is a heterocycle substituted by a ZNR9Rl0 group where Z is CH2, certain favoured compounds of formula ~[) may be prepared from a corresponding compound with a hydrogen atom in place of the ZNR9Rl0. Thus, for example a compound of the formula a) wherein Het is an imidazolinone group carrying a CH2NR9R1~ moiety may lo be prepared from a corresponding compound l~(~.king the CH2NR9Rl~
moiety by reaction with formaldehyde and an amine NHR9R10 under conventional ~nni~.h reaction conditions, for example in methanol with heating. If desired a pre-formed reagent such as R9R1~N+=CH2.I- may be employed and a tertiary amine such as triethylamine used as acid 1S acceptor.
Alternatively a compound of formula a) wherein Het is an imidazolinone group l~cking a CH2NR9Rl~ may be reacted with paraformaldehyde and an amine for example a secondary amine such as pyrrolidine to give a compound wherein the imidazolinone ring is substituted by CH2NR9R1~ where R9, R10 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom or a second nitrogen atom which will be part of a NH or NRC moiety, where Rc is as previously defined.
2s This reaction may be performed in a conventional manner, for instance, in a suitable solvent such as an alcohol, for example, methanol at an elevated temperature up to the boiling point of the solvent.
Intermediates of formula (II) may be prepared by reaction of a compound of formula (X[II) with a compound of formula (XIV):
CA 0221~700 1997-09-17 R4 Rs Rl HzN ~ ~ R RZ (XIV) (XIII) wherein R1, R2, R3, R4, R5, R7 and R3 are as defined in relation to formula (I) and LG is as previously defined. Preferably LG is a halogen atom, 5 expecially a bromine atom.
The reaction is effected in a conventional manner, for example in an organic solvent such as dimethylform~mide in the presence of a base such as, for example, an alkali metal hydride, such as sodium hydride.
Compounds of formula (XIII) may be prepared from known starting 0 materials by the reaction of a compound of formula (XV) with a compound of formula (~VI), followed by removal of the N-protecting group:
R4 Rs Rl ~ LG ~ R
HN ~ OH R8 R3 PG R
(XV) (XVI) 15 where LG is as previously defined and PG is a conventional amine protecting group, such as tert-butoxycarbonyl. The reaction is conveniently effected in a suitable organic solvent, such as dimethylformide in the presence of a base, such as, for example, an ~lkali metal hydride, such as sodium hydride. Removal of the protecting group CA 0221~700 1997-09-17 will depend upon the choice of protecting group. A tert-butoxycarbonyl group may be removed, for instance, using trifluoroacetic acid.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective C~roups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent 0 stage using methods known from the art.
The exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Spe-ific~t;on No.
WO 93/01165. The compounds were found to be active with IC50 at the NK1 receptor of less than 1~1M on said test method.
1S The following non-limiting Examples serve to illustrate the preparation of compounds of the present invention:
4-(N-((2-((3.5-Bis(trifluoromethyl)phenvl)methvloxy)- l-(S)-phenvl)ethyl-N-(2'-methoxvethvl))aminomethvl)-5-(N'.N'-dimethvlaminomethyl)- 1.2,3-triazole a) (2S)- 1-((3~5-Bis(trifluoromethvl)phenvl)methvloxv)-2-(2 methoxyethvlamino)-2 -phenvlethane L-2-Ammonium- 1-(3',5'-bis(trifluoromethyVphenyl)methyloxy-2-phenylethane (2g) was dissolved in (limethylform ~mi de (lOml). Sodium hydride (264mg, 60%) was added followed by 2-bromoethyl methyl ether (1.2g) and the mixture heated for 4 hours at 60~C. The reaction was quenched with water, extracted with ethyl acetate, washed with water (x2) and brine, dried (MgSO4) and evaporated i71 vacuo. The residue was purified on silica gel eluting with 10% ethyl acetate/petroleum ether (60-CA 0221~700 1997-09-17 W 096/Z9317 _34_ PCT/GB96/00586 80~C) to give the title compound. lH NMR (250MHz,CDCl3) ~ 2.09 (lH, vbr s), 2.59-2.75 (2H, m), 3.35 (3H, s), 3.42-3.50 (2H, m), 3.54-3.64 (2H, m), 3.97 (lH, m), 4.62 (2H, s), 7.25-7.41 (5H, m), 7.76 (2H, s), 7.79 (lH, s).
b) (2S)-1-((3.5-Bis(trifluoromethvl)Phenvl)methvloxy)-2-(N-(2'-methoxvethyl)-N-(4-chloro-2-butvne))amino-2 -phenvlethane The product from step (a) (0.6g) was dissolved in dimethylform~mi-l~ (6ml) and added dropwise to a pre-heated (60~C) solution of 1,4-dichloro-2-butyne (0.35g) and potassium carbonate (0.59g) o in dimethylformamide (6ml). The mixture was stirred for 4 hours and was then extracted with ethyl acetate and water. The organic layer was washed (H20, brine), dried (MgSO4) and evaporated in vacuo. The residue was purified on a gravity silica column using 10% ethyl acetate/petroleum ether (60-80~C) as eluant to give the title compound. lH NMR
(250MHz,CDC13) ~ 2.73 (2H, m), 3.23 (3H, s), 3.38 (2H, t, J=5.8Hz), 3.48 (lH, s), 3.56 (lH, s), 3.70-3.76 (lH, m), 3.81-3.91 (2H, m), 4.09 (2H, m), 7.19-7.29 (5H, m), 7.58 (2H, s), 7.68 (lH, s).
c) (2S)- 1-((3,5-Bis(trifluoromethvl)Phenvl)methvloxv)-2-(2'-methoxvethvl)-N-(4-azido-2-butvne)amino-2-Phenv] ethane -The product from step (b) (lOOmg) and sodium azide (16mg) were stirred together in dimethylsulfoxide under nitrogen for 16 hours. The reaction mixture was partitioned between ammonium chloride and ethyl acetate (4:1). The organic layer was washed (H2O, brine), dried (MgSO4) and evaporated in vacuo. The residue was purified on a gravity silica column using 20% ethyl acetate/ petroleum ether (60-80~C) as eluant to give the title compound. IH NMR (250MHz,CDCl3) ~ 2.72-2.81 (2H, m), 3.30 (3H, s), 3.41-3.48 (2H, m), 3.60 (lH, m), 3.62 (lH, br s), 3.75-4.00 (5H, m), 4.56 (2H, s), 7.26-7.40 (5H, m), 7.64 (2H, s), 7.75 (lH, s).
CA 0221~700 1997-09-17 d) 4-(N-((2-((3~5-Bis(trifluoromethvl)~henvl)methvloxv)- 1-(S)-phenvl)ethvl-N-(2'-methoxyethvl))aminomethvl)-5-(N',N'-dimethylaminomethvl)- 1.2,3-triazole The product from step (c) (lOOmg) and dimethylamine (0.5ml) in 1,4-dioxane (2ml) was heated with stirring in a sealed tube at 70~C for 5 hours. The reaction mixture was then cooled and evaporated in uacuo.
The residue was purified on a gravity silica column using 10%-20%
methanol/ethyl acetate as eluant to give the title compound. lH NMR
(250MHz,CDCl3) ~ 2.13 (6H, s), 2.~6-2.75 (lH, m), 2.82-2.92 (lH, m), 3.27 0 (3H, s), 3.37-3.44 (4H, m), 3.77-3.83 (2H, m), 3.88-3.9(~ (2H, m), 4.05 (lH, t, J=(~.29Hz), 4.54 (2H, s), 7.19-7.27 (5H, m), 7.G4 (2H, s), 7.72 (lH, s). MS
(ES) = 559.
This invention relates to a class of heteroaromatic compounds which s are useful as tachykinin antagonists.
The tachykinins are a group of naturally occurring peptides found widely distributed throughout m~mm~ n tissues, both within the central nervous system and in peripheral nervous and circulatory systems.
The tachykinins are distinguished by a conserved carboxyl-terminz~l o sequence: I
Phe-X-Gly-Leu-Met-NH2 At present, there are three known m~mm~ n tachykinins referred to as substance P, neurokinin A (NKA, substance K, neuromedin L) and neurokinin B (NKB, neuromedin K) (for review see J.E. Maggio, Peptides (1985) 6(suppl. 3), 237-242). The current nomenclature (le.cign~tes the three tachykinin receptors mediating the biological ~rtion~ of substance P, NKA and NKB as the NK1, NK2 and NK3 receptors, respectively.
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic infl ~mm ~tory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, ;nfl~mm~tory diseases of the gut including ulcerative colitis and Crohn's disease, ocular 2~ injury and ocular infl~mm~tory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyper-reflexia is reviewed in "Tachykinin Receptors and Tachykinin Receptor Antagonists", C.A. Maggi, R.
Pat~crl-ini, P. Rovero and A. Giachetti, J. Auto7z. Pharmacol. (1993) 13, 23-93.
CA 0221~700 1997-09-17 W 096/29317 2 PCT/GB~6/00586 For instance, substance P is believed inter alia to be involved in the neurotr~n.smi.s.sion of pain sensations [Otsuka et al, "l~ole of Substance P
as a Sensory 'rr~n.smitter in Spinal Cord and Sympathetic Ganglia" in 1982 Substance P i71 the Nervous System, Ciba Foundation Symposium 91, 13-34 (published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Act as a Pain Tr~n.smitter?" TIPS (1987) 8, 506-510], sperificc~lly in the tr~n.smi.s.qion of pain in migraine (E,.E.B. Sandberg et al, J. Med Chem, (1982) 25, 1009) and in arthritis [Levine et al Science (1984) 226, 547-549]. Tachykinins have also been implicated in gastrointestinal 0 (GI) disorders and diseases of the GI tract such as infl~mm~tory bowel disease [Mantyh et al Neuroscience (1988) 25(3), 817-37 and D. Regoli in "Trends in Cluster Headache" Ed. Sicuteri et al Elsevier Scientific Publishers, Amsterdam (1987) page 85)] and emesis [F. D. Tatter.s~ll et al, Eur. J. Pharmacol., (1993) 250, R5-R6]. It is also h.ypothesised that there is a neurogenic merh~ni.sm for arthritis in which substance P may play a role [Kidd et al "A Neurogenic Merh~ni.sm for Symmetrical Arthritis" in The Lancet, 11 November 1989 and Gronblad et al, "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J.
Rheumatol. (1988) 15(12), 1807-10]. Therefore, substance P is believed to be involved in the infl~mm~tory response in diseases such as rheumatoid arthritis and osteoarthritis, and fibrositis [O'Byrne et al, Arthritis and Rheumatism (1990) ~, 1023-8]. Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions [Hamelet et al, Ca71. J. Pharmacol. Physiol. (1988) 66, 1361-7], immunoregulation [Lotz et al, Science (1988) 241, 1218-21 and ~imball et al, J. Immunol. (1988) 141(10), 3564-9] vasodilation, bronchospasm, reflex or neuronal control of 7 the viscera p~antyh et al, PNAS (1988) 85, 3235-9] and, possibly by arresting or slowing ~-amyloid-mediated neurodegenerahve changes [Yankner et alJ Science (1990) 250, 279-82] in senile dementia of the Alzheimer type, Alzheimer's disease and Down's Syndrome.
CA 0221~700 1997-09-17 Tachykinin antagonists may also be useful in the treatment of small cell carcinomas, in particular small cell lung cancer (SCLC) Langdon et al, Cancer Research (1992) 52, 4~54-7].
Substance P may also play a role in demyelinating diseases such as s multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et al, poster C.I.N.P. XVlIIth Congress, 28th June-2nd July 1992], and in disorders of blz3~ r filnction such as bladder detrusor hyper-r-?flç~i~
(Lancet, 16th May 1992, 1239).
It has furthermore been suggested that tachykinins have utility in 0 the following disorders: depr~ ior-, dysthymic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as ~ngin?~ and Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fasri~ i.c, reflex sympathetic dystrophy such as shoulder/hand syndrome, a~lrliction 5 disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorders related to immune çnll~nc~ment or suppression such as systemic lupus erythmatosus (European patent specification no. 0 436 334), ophtl~lmic disease such as conjuctivitis, vernal conjunctivitis, and the like, and cutaneous diseases such as contact dermatitis, atopic 20 dermatitis, urtic~ri~, and other eczematoid dermatitis (European patent specification no. 0 394 989).
European patent spe-ifir~tion no. O B77 394 (published 5th January 1994) discloses morpholine and thiomorpholine tachykinin receptor antagonists of the general formula R3~ X ~ R
R2~ J~ N J' R
R
wherein Rln is a large variety of substituents;
R2U and R3~ are inter alia hydrogen;
R4" is inter alia CA 0221~700 1997~09~17 ~R~-R5a is inter alia optionally substituted phenyl;
R6a, R7a and R3a are a variety of substituents;
XaisO,S,SOorSO2;
yaiS inter alia O; and ZaiS hydrogen or Cl 4alkyl.
We have now found a further class of non-peptides which are potent antagonists of tachykinins, especially of substance P.
The present invention provides compounds of the formula a):
Het N~ ~R2 OMe (I) wherein Rl represents hydrogen, halogen, Cl.6alkyl2 C2.6alkenyl, C2.6alkynyl, 15 C3.7cycloalkyl, C3.7cycloalkylCl-4alkyl, Cl.6alkoxy, Cl.~alkyl substituted by a hydroxy or Cl.4alkoxy group, OCF3, hydroxy, tri~luoromethyl, trimethylsilyl, nitro, CN, SRa, SORa, SO2RQ, CORa, CO2Ra or CONRaRb where Ra and Rb are each independently hydrogen or Cl.4alkyl;
R2 and R3 each independently represent hydrogen, halogen, 20 Cl.6alkyl, Cl.6alkoxy substituted by a Cl.4alkoxy group, or trifluoromethyl;
CA 0221~700 1997-09-17 R4 represents hydrogen, halogen, C1 6alkyl, C2.6alkenyl, C2.6aIkynyl, C3.7cycloalkyl, C3.7cycloalkylC1.4alkyl, C1.6alkoxy, C1.4alkyl substituted by a hydroxy or C1.4alkoxy group, OCF3, hydroxy, trifluoromethyl, trimethylsilyl, nitro, CN, SRs, SORA, SO2RA, CORA, CO2Ra, CONRsRb where RA and Rb are as previously defined;
R5 represents hydrogen, halogen, C1.6alkyl, C1.6alkoxy substituted by a C1.4alkoxy group, or trifluoromethyl;
R6, R7 and R3 each independently represent hydrogen or a Cl.4alkyl group optionally substituted by a hydroxy group;
Het represents a 5- or 6-membered heterocyclic ring cont~ining 2 or 3 nitrogen atoms optionally substituted by =O, =S or a Cl.4~1kyl group, and optionally substituted by a group of the formula ZNR9Rl0 where Z is C1.6alkylene or C3.6cycloalkyl;
R9 is hydrogen or C,.4alkyl, C3.7cycloalkyl, C3.7cycloalkylC1.4alkyl, or C2.4alkyl substituted by C1.~alkoxy or hydroxyl;
R10 is hydrogen or C1.4alkyl, C3.7cycloalkyl, C3.7cycloalkylC1.4alkyl, or C2.4alkyl substituted by C1 1~lko~y, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R9, R10 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy or Cl.4alkoxy optionally substituted by a Cl.4alkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH
or NRC moiety where Rc is Cl.4alkyl optionally substituted by hydroxy or Cl.4alkoxy;
or R9, R10 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
CA 022l~700 l997-09-l7 W 096/29317 ~ PCT/GB96/00586 or Z, R9 and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which may optionally cont~in an oxygen ring atom;
and pl~rm~ceutically acceptable salts thereof.
Certain particularly apt compounds of the present invention include those wherein Rl is hydrogen, Cl 4alkyl, Cl.4alkoxy, h~logen or CF3.
Most aptly R2 is hydrogen, Cl.4alkyl, Cl ,alkoxy, halogen or CF3.
Most aptly R3 is hydrogen, fluorine, chlorine or CF3.
Favourably Rl is fluorine, (~hlf)rine or CF3.
o Favourably R2 is hydrogen, fluorine, chlorine or CF3.
Favourably R3 is hydrogen, fluorine, chlorine or CF3.
Preferably Rl and R2 are in the 3 and 5 positions of the phenyl ring.
More preferably, Rl is 3-fluoro or 3-CF3.
More preferably, R2 is 5-fluoro or 5-CF3.
More preferably, R3 is hydrogen.
Most preferably, Rl is 3-F or 3-CF3, R2 is 5-F or 5-CF3 and R3 is hydrogen.
Most aptly R4 is hydrogen.
Most aptly R5 is hydrogen, fluorine, chlorine or CF3.
Preferably R4 is hydrogen and R5 is hydrogen or 4-fluoro.
Most aptly R6 and R7 are each independently hydrogen or methyl.
Preferably R6 is hydrogen. Preferably R~ is hydrogen. Most preferably R3 and R7 are both hydrogen.
Most aptly R3 may be hydrogen or Cl.2alkyl optionally substituted by a hydroxy group. In particular, R3 may be hydrogen, methyl or hydroxymethyl.
Favourably Het is a 5-membered ring.
In particular, Het may represent a heterocyclic ring selected from:
-<\ ~ ; <\ ~ ; N~ ~ ;
N N N
z NR9Rl O
N ZNR R ~ ; and <
Particularly preferred heterocyclic rings represented by R6 are selected from:
H H H
N ~ N ~ ~ N ~
H H_N N ZNR9Rl0 H ~ ,N ~ ; and <
N ZNR R N ZNR R N
z NR9Rl O
Most especially, Het may represent a heterocyclic ring selected from:
H H
<~ ~ ; O ~ ~ ,N ~
N ZNR R N ZNR9Rl0 N ZNR R
A particularly preferred heterocyclic ring represented by Hetis:
CA 0221~700 1997-09-17 W 096/29317 8 PCT/GB~C/C~'8 N
HN~ ~
N ZNR9Rl0 With respect to compounds of the formula a), Z may be a linear, branched or cyclic group. Favourably Z contains 1 to 4 carbon atoms and 5 most favourably 1 or 2 carbon atoms. A particularly favourable group Z is CH2 .,.
With respect to compounds of the formula (I), R9 may aptly be a Cl-4alkyl group or a C2.4alkyl group substituted by a hydroxyl or Cl.2alkoxy group, Rl~ may aptly be a Cl 4alkyl group or a Cl.4alkyl group substituted o by a hydroxyl or Cl 2alkoxy group, or R9 and Rl~ may be linked so that, together with the nitrogen atom to which they are attached, they form an azetidinyl, pyrrolidinyl, piperidyl, morpholino, thiomorpholino, piperazino or piperazino group substituted on the nitrogen atom by a Cl.4alkyl group or a C2.4alkyl group substituted by a hydroxy or Cl.2alkoxy group.
Where the group NR9Rl0 represents a heteroaliphatic ring of 4 to 7 ring atoms and said ring cont~inq a double bond, a particularly preferred group is 3-pyrroline.
Where the group NR9Rl0 represents a non-aromatic azabicyclic ring system, such a system may contain between 6 and 12, and preferably 20 between 7 and 10, ring atoms. S~ hl~ rings include 5-azabicyclo[2. 1. l]hexyl, 5-azabicyclo[2.2. l]heptyl, 6-azabicyclo[3.2. l]octyl, 2-azabicyclo[2.2.2]octyl, 6-azabicyclot3.2.2]nonyl, 6-azabicyclo[3.3.1]nonyl, 6-azabicyclo[3 .2 .2] decyl, 7-azabicyclo[4.3 .1] decyl, 7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially 2~ 5-azabicyclo[2.2.1]heptyl and 6-azabicyclo[3.2.1]octyl.
Where Rl~ represents a C2 4alkyl group substituted by a 5 or 6 membered heteroaliphatic ring cont~ining one or two heteroatoms selected from N, O and S, suitable rings include pyrrolitlino, pipçri-lino, piperazino, morpholino, or thiomorpholino. Particularly plef~rled are nitrogen CA 0221~700 1997-09-17 cont~inin~ heteroaliphatic rings, especially pyrrolidino and morpholino r~gs.
Particularly suitable moieties ZNR9Rl0 include those wherein Z is CH2 or CH2CH2 and NR9R'0 is amino, methylamino, dimethylamino, s diethylamino, azetidinyl, pyrrolidino and morpholino.
Further preferred moieties represented by ZNR9Rl0 are those wherein Z is CH2 or CH2CH2, R9 represents hydrogen, Cl.4~1kyl or C3.6cycloalkyl and Rl~ is C2.4alkyl substituted by one or two substituents selected from hydroxy, Cl.2alkoxy, azetidinyl, pyrrolidino, piperidino, 0 morpholino or thiomorpholino.
In particular, Z is preferably CH2 and NR9Rl0 is preferably dimethylamino, azetidinyl or pyrrolidino, especially dimethyl~mino.
As used herein, the term "alkyl" or "alkoxy" as a group or part of a group means that the group is straight or branched. F.x~mples of suitable ~lkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. F,x~mples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
The cycloalkyl groups ~ efer- ed to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A sllit~hle cycloalkylalkyl group may be, for example, cyclopropylmethyl.
As used herein, the terms "~lkenyl" and "alkynyl" as a group or part of a group means that the group is straight or branched. Examples Gf suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is propargyl.
When used herein the term halogen means fluorine, chlorine, bromine and iodine. The most apt halogens are fluorine and ~hlorine of which fluorine is preferred.
One favoured group of compounds of the present invention are of the formula (Ia):
CA 0221~700 1997-09-17 ~ A
"'" N O ~ A
OMe (Ia) wherein R8 and Het are as defined in relation=to formula a) and Al is fluorine or CF3;
A2 is fluorine or CF3; and A3 is hydrogen or fluorine;
and ph~rm~ceutically acceptable salts thereo~
Specific compounds within the scope of this invention include:
4-(N-((2-((3,5-bis(trifluoromethyVphenyvmethyloxy)- l-(S)-phenyl)ethyl-N-10 (2'-methoxyethyl))aminomethyV-5-(N',N'-dimethylaminomethyV-1,2,3-triazole;
and pharmaceutically acceptable salts thereof.
In a further aspect of the present invention, the compounds of formula a) will preferably be prepared in the form of a ph~rm~eutically 15 acceptable salt, especially an acid addition salt.
For use in medicine, the salts of the compounds of formula a) wi~l be non-toxic pl~rm~ceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. S~ hle 20 ph~rm~ceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mi~ing a solution of the compound according to the invention with a solution of a p~rm~( eutically acceptable acid such as hydrochloric acid, filmz~ric acid, p-toluenesulphonic acid, maleic acid, suc(~inic acid, acetic acid, citric acid, CA 0221~700 1997-09-17 tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of s the invention carry an acidic moiety, suitable ph~rm~reutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g.
sodium or potassium salts; and ~lk~line earth metal salts, e.g. calcium or magnesium salts.
The salts may be formed by conventional means, such as by reacting lO the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed i71 uacuo or by freeze drying or by ~x~ nging the anions of an existing salt for another anion on a suitable ion exchange resin.
The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula a) which are readily convertible in vivo into the required compound of formula (I).
Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
A prodrug may be a pl~rm~ologically inactive derivative of a biologically active substance (the "parent drug" or "parent molecule") that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible function~lity.
The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.
CA 022l~700 l997-09-l7 The compounds according to the invention have at least three asymmetric centres, and may accordingly exist botll as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present 5 invention.
The preferred compounds of the formula (I) will have the pleLerled stereochemistry as shown in formula (Ib) ~S Rl R6 ~ ~ R
OMe (Ib) The present invention further provides ph~rm~ceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable callier or excipient.
Preferably the compositions according to the invention are in unit 15 dosage forms such as tablets, pills, capsules, powde~rs, granules, solutions or susp~n~ion~, or suppositories, for oral, parenter~l or rectal a-lmini.ctration, or a~lmini~tration by inh~l~tion or insufflation.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a ph~rm~ceutical carrier, e.g. conventional 20 tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, ~icalcium phosphate or gums, and other ph~rm~ceutical diluents, e.g. water, to form a solid preformulation composition cont~ining a homogeneous mixture of a compound of the present invention, or a non-toxic ph~rm~eutically acceptable salt thereo~
CA 0221~700 1997-09-17 When r~ferring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
This solid preformulation composition is then subdivided into unit dosage forms of the type described above cont~ining from 0.1 to about ~00 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, 0 the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
The two components can be separated by an enteric layer which serves to resist disintegration in the stom~(~h and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and ce~lulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for a-lmini.stration orally or by injection 20 include aqueous solutions, suitably flavoured syrups, aqueous or oil suspen.sion.s, and flavoured emlll.sion.s with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and .simil~r ph:~rm~ceutical vehicles. Sllit~hle. dispersing or suspending agents for aqueous susp~n.sions include synthetic and natural gums such as tragacanth, ~c~ l gin ~te, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Preferred compositions for a-lmini.stration by injection include those comprising a compound of formula a), as the active ingredient, in association with a surface-active agent (or wetting agent or sllrf~ct~nt) or 30 in the form of an emulsion (as a water-in-oil or oil-in-water emulsion).
CA 0221~700 1997-09-17 Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. TweenTM 20, 40, ~;0, 80 or 85) and other sorbitans (e.g. SpanTM 20, 40, 60, 80 or 86). Compocition.~
with a surface-active agent will conveniently comprise between 0.06 and 5% surface-active agent, and preferably between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example m~nnitol or other pharmaceutically acceptable v~hirle.~, if necessary.
Sl-it~hle emulsions may be prepared using commercially av~ hle fat emulsions, such as Intralipid , Liposyn , InfonutrolTM, LipofundinTM
o and LipiphysanTM. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g.
egg phospholipids, soybean phospholipids or soybean, lecithin) and water.
It will be appreciated that other ingredients may be added, for example gylcerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion will preferably comprise fat droplets between 0.1 and l.O~lm, particularly 0.1 and 0.5,um, and have a pH in the range of 5.5 to 8Ø
Particularly preferred emulsion compositions are those prepared by mixing a compound of formula a) with IntralipidTM or the components thereof (soybean oil, egg phospholipids, glycerol and water).
Compositions for inh~l~tion or insu~lation include solutions and suspen.~i-ns in ph~rm~eutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compo.ci~ion.s may contain suitable pharmaceutically acceptable excipients as set out above.
Preferably the compositions are a-lmini~tered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably 30 sterile ph~rm~eutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the CA 0221~700 1997-09-17 nebulising device or the nebllli.qing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be a.iminiqtered, preferably orally or nasally, from devices which deliver the formulation in an appropriate s manner.
The present invention futher provides a process for the preparation of a p~rm~(~eutical composition comprising a compound of formula a), which process comprises bringing a compound of formula a) into association with a pharmaceutically acceptable carrier or excipient.
o The compounds of formula a) are of value in the treatment of a wide variety of rlini~l conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity.
Thus, for example, an excess of tachykinin, and in particular substance P, activity is implicated in a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific ~nim~l phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-trallm~tic stress disorder and acute stress disorder, and generalised anxiety disorders; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallucinations; delerium, dementia, and ~ amnestic and other cognitive or neurodegenerative disorders, such as Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, vascular dementia, and other dementias, for example, due to HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, CA 0221~700 1997-09-17 W 096/29317 1~ - PCT/GB96/00~86 Creutzfeldt-Jakob disease, or due to multiple aetiologies; Parkinson's disease and other extra-pyr~mi~l~l movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced parkinsonism, neuroleptic m~ n~nt syndrome, neuroleptic-induced acute s dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremour; substance-related disorders ~ricing from the use of alcohol, amphetamines (or amphet~mine-like substances) caffeine, c~nn~hi.~, cocaine, hallucinogens, inh~l~nts and aerosol propellants, nicotine, opioids, phenylglycidine derivatives, o sedatives, hypnotics, and anxiolytics, which substance-related disorders include dependence and abuse, intoxication, withdrawal, intoxication delerium, withdrawal delerium, persisting dementia, psychotic disorders, mood disorders, anxiety disorders, sexual dysfunction and sleep disorders;
epilepsy; Down's syndrome; demyelinating diseases such as MS and ALS
5 and other neuropathological disorders such as peripheral neuropathy, for example diabetic and chemotherapy-induced neuropathy, and postherpetic neuralgia, trig~min~l neuralgia, segmental or intercostal neuralgia and other neuralgias; and cerebral vascular disorders due to acute or chronic cerebrovascular damage such as cerebral infarction, subarachnoid 20 haemorrhage or cerebral oedema.
Tachykinin, and in particular substance P, activity is also involved in nociception and pain. The compounds of the present invention will therefore be of use in the prevention or treatment of diseases and conditions in which pain pre(lomin~tes, including soft tissue and 2s peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, episiotomy pain, and burns; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for 30 example, dysmenorrhoea, and labour pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for CA 0221~700 1997-09-17 example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, tic douloureux, atypical facial pain, nerve root damage, and arachnoiditis; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage; low back pain; sciatica; ankylosing spondylitis, gout; and scar pain.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive o airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm;
infl:~mm~tory diseases such as infl~mmatory bowel disease, psori~ci~
fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn;
allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; opht}~lmiG conditions associated with cell proliferation such as proliferative vitreoretinopathy; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of neoplasms, including breast tumours, neuroganglioblastomas and small cell carcinomas such as small cell lung cancer.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of gastrointestinal (GI) disorders, including infl~mm~tory disorders and diseases of the GI tract such as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disorders associated with the neuronal control of viscera, ulcerative colitis, (~rohn's disease, irritable bowel syndrome and emesis, including acute, delayed or anticipatory emesis such as emesis induced by chemotherapy, ra~ tion, toxins, viral or bacterial infections, pregn~ncy, vestibular disorders, for CA 0221~700 1997-09-17 example, motion sickness, vertigo, dizziness and Meniere's disease, ~ul ~e. ~, migraine, variations in intercranial pressure, gastro-oesophageal reflux disease, acid indigestion, over indulgence in food or drink, acid stomach, waterbrash or regurgitation, heartburn, for example, episodic, nocturnal or meal-induced heartburn, and dyspepsia.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of a variety of other conditions including stress related somatic disorders; reflex sympathetic dystrophy such as shoulderlhand syndrome; adverse immunological reactions such as o rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosus;
plasma extravasation resulting from cytokine chemotherapy, disorders of bladder function such as cystitis, bladder detrusor hyper-reflexia and incontinence; fibrosing and collagen diseases such as scleroderma and 1S eosinophilic fasl~ioli~sis; disorders of blood ~low caused by vasodilation and vasospastic diseases such as ~n~ina, vascular headache, migraine and Reynaud's disease; and pain or nociception attributable to or associated with any of the foregoing conditions, especially the tr~n.smi.s.sion of pain in migraine.
The compounds of formula a) are also of value in the treatment of a combination of the above conditions, in particular in the treatment of comhined post-operative pain and post-operative nausea and vl miting The compounds of formula (I) are particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. Most especially, the compounds of formula ~[) are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents including those routinely used in cancer chemotherapy.
F',~mples of such chemotherapeutic agents include alkylating agents, for example, nitrogen mustards, ethyleneimine compounds, alkyl CA 0221~700 1997-09-17 sulphonates and other compounds with an alkylating action such as nitrosoureas, cisplatin and dacarbazine; antimetabolites, for example, folic acid, purine or pyrimidine antagonists; mitotic inhibitors, for example, vinca ~lk~loids and derivatives of podophyllotoxin; and cytotoxic s antibiotics.
Particular examples of chemotherapeutic agents are described, for instance, by D. J. Stewart in Nausea and Vomiti7~g: Recent Research and Clinical Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton, Florida, USA (1991) pages 177-203, especially page 188. Commonly used 0 chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil [R. J. Gralla et al in Cancer Treatme7lt Reports (1984) 68(1), 1~3-172].
The compounds of formula a) are also of use in the treatment of emesis induced by radiation including radiation therapy such as in the treatment of cancer, or radiation sickness; and in the treatment of post-operative nausea and vomiting.
It will be appreciated that the compounds of formula (I) may bepresented together with another therapeutic agent as a combined preparation for simultaneous, separate or sequential use for the relief of emesis. Such combined preparations may be, for example, in the form of a twin pack.
A further aspect of the present invention comprises the compounds of formula O in combination with a 5-HT3 antagonist, such as ondansetron, granisetron or tropisetron, or other anti-emetic medicaments, for example, a dopamine antagonist such as 30 metoclopramide. Additionally, a compound of formula (I) may be a-lmini.~tered in combination with an anti-infl~mmatory corticosteroid, CA 0221~700 1997-09-17 W Og6/29317 20 PCT/GB96/00586 such as dexamethasone. Furthermore, a compound of formula a) may be a-lmini.~tered in combination with a chemotherapeutic agent such as an aLkylating agent, antimetabolite, mitotic inhibitor or cytotoxic antibiotic, as described above. In general, the currently av~ hle. dosage forms of the s known therapeutic agents for use in such combinations will be suitable.
When tested in the ferret model of cisplatin-induced emesis (le.~r.rihed by F. D. Tattersall et al, in Eur. J. pharmacol., (1993) 250, R5-R6, the compounds of the present invention were found to attenuate the retching and vomiting induced by cisplatin.
o The compounds of formula (I~ are also particularly useful in the treatment of pain or nociception and/or infl~mm~tion and disorders associated therewith such as, for example, neuropathy, such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis and headache, 1S including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and m~ ry sinus pain,.
The present invention further provides a compound of formula (I) for use in therapy.
According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P.
The present invention also provides a method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises a~mini.~tration to a patient in need thereof of a tachykinin reducing amount of a compound of formula (I) or a composition comprising a compound of formula (I).
For the treatment of certain conditions it may be desirable to employ a compound according to the present invention in conjunction with another ph~rm~ologically active agent. For example, for the treatment of CA 0221=,700 1997-09-17 respiratory diseases such as asthma, a compound of formula a) may be used in conjllnct;on with a bronchodilator, such as a ~,2-adrenergic receptor antagonist or tachykinin antagonist which acts at NK-2 receptors. The compound of formula a) and the bronchodilator may be 5 a-lmini.qtered to a patient simultaneously, sequentially or in combination.
Likewise, a compound of the present invention may be employed with a leukotriene antagonists, such as a leukotriene D4 antagonist such as a compound selected from those disclosed in European patent specification nos. 0 480 717 and 0 604 114 and in US patent nos. 4,859,692 lo and 5,270,324. This combination is particularly useful in the treatment of respiratory diseases such as asthma, chronic bron~ itis and cough.
The present invention accordingly provides a method for the treatment of a respiratory disease, such as asthma, which method comprises a-lmini.stration to a patient in need thereof of an effective amount of a compound of formula a) and an effective amount of a bronchodilator.
The present invention also provides a composition comprising a compound of formula a), a bronchodilator, and a ph~rm~ceutically acceptable carrier.
It will be appreciated that for the treatment or prevention of migraine, a compound of the present invention may be used in conjunction with other anti-migraine agents, such as ergotamines or 5-HTl agonists, especially sumatriptan.
Likewise, for the treatment of behavioural hyperalgesia, a 2~i compound of the present invention may be used in conjunction with an antagonist of N-methyl D-aspartate (NMDA), such as dizocilpine.
For the treatment or prevention of infl~mm~tory conditions in the lower urinary tract, especially cystitis, a compound of the present invention may be used in conjunction with an anti-infl ~mm ~tory agent such as a bradykinin receptor antagonist.
The present invention also provides a composition comprising a compound of formula a), a bronchodilator, and a ph ~rm ~ceutically acceptable C~r~ r.
It will be appreciated that for the treatment or prevention of pain or nociception, a compound of the present invention may be used in conjunction with other analgesics, such as acetaminophen (paracetamol), aspirin and other NSAIDs and, in particular, opioid analgesics, especially morphine. Specific anti-infl~mm~tory agents include diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, piroxicam and sulindac.
o Suitable opioid analgesics of use in conjunction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydLromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereo~ Preferred salts of these opioid analgesics include morphine sulphate, morphine hydrochloride, morphine tartrate, codeine phosphate, codeine sulphate, dihydrocodeine bitartrate, diacetylmorphine hydrochloride, hydrocodone bitartrate, hydromorphone hydrochloride, levorphanol tartrate, oxymorphone hydrochloIide, alfentanil hydrochloride, buprenorphine hydrochloride, butorphanol tartrate, fentanyl citrate, meperidine hydrochloride, methadone hydrochloride, nalbuphine hydrochioride, propoxyphene hydrochloride, propoxyphene napsylate (2-naphthalenesulphonic acid (l: l) monohydrate), and pentazocine hydrochloride.
Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and CA 0221~700 1997-09-17 an analgesic as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of pain or nociception.
The excellent pharmacological profile of the compounds of the present invention offers the opportunity for their use in therapy at low doses thereby minimi.~ing the risk of unwanted side effects.
In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day.
o For example, in the treatment of conditions involving the neurotr~n~miq.cion of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be arlmini~tered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of emesis using an injectable formulation, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 1 mg/kg per day. The compounds may be a-lmini.~tered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be appreciated that the amount of a compound of formula (V
required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of a(lmini~tration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.
According to a general process (A), the compounds according to the invention may be prepared from compounds of formula (IV
CA 022l5700 l997-09-l7 OMe (II) wherein Rl, R2, R3, R4, R5, RG, R7 and R3 are as defined in relation to formula a) by reaction with a compound of formula (IIV:
LG-CH2-Het' (III) where Het' is a group of the formula Het as defined in relation to formula 0 (I) or a precursor therefor and LG is a leaving group such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g.
bromine, chlorine or iodine); and, if Het' is a precursor group, converting it to a group Het (in which process any reactive group may be protected and thereafter deprotected if desired).
This reaction may be performed in conventional manner, for example in an organic solvent such as dimethylform~mide in the presence of an acid acceptor such as potassium carbonate.
Thus, for instance, compounds in which Het is a 2-oxo- 1,3-imidazolyl, 1,3-imidazolyl or 1,2,3-triazolyl group, each of which is 20 substituted by ZNR9Rl0, may be prepared by the reaction of a compound of formula (II) with a compound of formula aV) CA 0221~700 1997~09~17 W 096/29317 -25 ~ PCT/GB96/00~86 LG LG LG
(CH~)n H (CH2)~ H (c) HN~ ~
LG LG LG
(IV) where n is an integer from 1 to ~, and each LG independently represents a leaving group as previously defined, followed by reaction of the resultant s compound with an amine of formula NHR9Rl0 to complete the group ZNRsRlo It will be appreciated that, where necessary, reactive groups may be protected, thus for example, the NH groups of an imidazolone of formula (IVa) may be protected by any suitable amine protecting group such as an lo acetyl group .
According to another process (B), compounds of formula (I) wherein Het represents 1,2,3-triazol-4-yl substituted by CH2NR9Rl~, may be prepared by reaction of a compound of formula (V) R ~ R Rl ~R9RI0 R ~ ~R2 OMe (V) 1~
with an azide, for example, sodium azide in a suitable solvent such as dimethylsulphoxide at a temperature of between 40~C and 100~C, followed CA 0221~700 1997-09-17 W 096/29317 2~ PCT/G~G/o~r86 by reduction of the carbonyl group adjacent to -NR9Rl0 using a suit~hle reducing agent such as lithium aluminium hydride at at a temperature between -10~C and room temperature, conveniently at room temperature.
Alternatively, according to a process (C), compounds of formula ~
wherein Het represents 1,2,3-triazol-4-yl substituted by CH2NR9Rl~, may be prepared by reaction of a compound of formula (Vl) ~0 OMe (VI) o with an amine of formula NHR9Rl0, in a suitable solvent such as an ether, for example, dioxan, at elevated temperature, for example, between 50~C
and 100~C, in a sealed tube, or the like. This reaction is based upon that described in Chem ische Berichte (1989) 122, p . 1963 .
According to another process, (D), compounds of formula (I) wherein 15 Het represents substituted or unsubstituted 1,3,5-tti~7.ine may be prepared by reaction of intermediates of formula (VII):
R5 Rl N ~ ~ R3R2 NH2 ~ R R
OMe (VII) with substituted or unsubstituted 1,3,5-t.ri~7.ine.
The reaction is conveniently effected in a suitable organic solvent, 5 such as acetonitrile, at elevated temperature, such as 80-90~C, preferably about 82~C.
According to a further process, (E), compounds of formula (V
wherein Het represents substituted or unsubstituted 1,2,4-t.ri~7.ine may be prepared by reaction of an intermediate of formula (VIIV with a 0 dicarbonyl compound of formula (IX):
~7 ~RRZ R,sJb,H
H2NHN 6)~ R R o OMe (VIII) (IX) wherein R35 represents H or a suitable substituent such as ZNR9Rl0.
lS The reaction is conveniently effected in a suitable organic solvent, such as an ether, e.g. tetrahydrofuran, conveniently at ~mbient temperature.
CA 0221~700 1997-09-17 According to a further process a~), compounds of formula wherein Het represents a substituted 1,2,4-triazolyl group may be prepared by reaction of an intermediate of formula aI) with a compound of formula (X) J~NHI~ Hal (X) wherein Hal is a halogen atom, for example, bromine, ~hlorine or io-line and Rl8 is H, CONH2 or OCH3 (which is converted to an oxo substituent under the reaction conditions), in the presence of a base, followed where necessary by conversion to a compound of formula a), for example, by 0 reduction of the CONH2 group to CH2NH2.
Suitable bases of use in the reaction include alkali metal carbonates such as, for example, potassium carbonate. The reaction is conveniently effected in an anhydrous organic solvent such as, for example, anhydrous dimethylformamide, preferably at elevated temperature, such as about 140~C.
A suitable reducing agent for the group CONH,;, is lithium aluminium hydride, used at between -10~C and room temperature.
According to another process, (G), compounds of formula a) wherein Het represents thioxotriazolyl may be prepared from intermediates of 20 formula (XI) CA 0221~700 1997-09-17 R Rl -R
~ N ~ ~ R3 H2NHN R6 ~ R R
OMe (XI) by reaction with a compound of formula HNCS, in the presence of a base.
Suitable bases of use in the reaction include organic bases such as, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene a)BU). The reaction is 5 conveniently effected in a suitable organic solvent, such as alcohol, e.g.
butanol.
Further details of suitable procedures will be found in the accompanying Fx~mples.
Intermediates of formula (V) may be prepared from intermediates of 0 formula aI) by reaction with an acetylene compound of formula HC_C~-CH2-Hal in the presence of a base such as potassium carbonate in a suitable solvent such as dimethylform~mide, conveniently at room temperature, followed by reaction of the resultant acetylene intermediate with an amide of formula Hal-CO-NR9Rl0 in the presence of suitable 15 catalysts including bis(triphenylphosphine) palladiumaI) chloride, coppera) iodide and triphenylphosphine in a suitable solvent such as triethylamine, preferably at reflux.
Intermediates of formula (VI) may be prepared from a compound of formula (XII) CA 0221~700 1997-09-17 ~R6 Hal OMe (XII) wherein Hal is a halogen atom, for example, rhlorine, bromine or iodine, especially rhlorine, by reaction with an azide, for example, sodium azide in a sllit~hle solvent such as dimethylsulphoxide at or below room 5 temperature.
Compounds of formula (XII) may be prepared by a dropwise addition of an intermediate of formula aI) to a dihaloacetylene of formula Hal-CH2-C_C-CH2-Hal where each Hal is independently chlorine, bromine or io(line, especially rhlorine. The reaction is conveniently effected in a suitable solvent such as dimethylform~mide in the presence of a base such as potassium carbonate.
Intermediates of formula (VII) may be prepared from intermediates of formula aI) by reaction with a compound of formula Hal-CH2-C(NH)NH2, where Hal is as previously defined.
1~ Intermediates of formula (VIII) may be prepared from intermediates of formula aI) by reaction with a compound of formula Hal-CH2-C(NH)NHNH-Boc, wherein Hal is as previously defined and Boc stands for t-butoxycarbonyl, followed by deprotection under acidic conditions.
Compounds of formula ax) are commercially available or may be prepared from commercially av~ hle compounds by known methods.
Compounds of formula (X) may be prepared as described in J. Med. Chem., (1984) 27, 849.
CA 0221~700 1997-09-17 Intermediates of formula (XI) may be prepared from the corresponding ester by treatment with hydrazine. The reaction is conveniently effected in a suitable organic solvent, such as an alcohol, for example, ethanol, at elevated temerpature.
s For compounds wherein Het is a heterocycle substituted by a ZNR9Rl0 group where Z is CH2, certain favoured compounds of formula ~[) may be prepared from a corresponding compound with a hydrogen atom in place of the ZNR9Rl0. Thus, for example a compound of the formula a) wherein Het is an imidazolinone group carrying a CH2NR9R1~ moiety may lo be prepared from a corresponding compound l~(~.king the CH2NR9Rl~
moiety by reaction with formaldehyde and an amine NHR9R10 under conventional ~nni~.h reaction conditions, for example in methanol with heating. If desired a pre-formed reagent such as R9R1~N+=CH2.I- may be employed and a tertiary amine such as triethylamine used as acid 1S acceptor.
Alternatively a compound of formula a) wherein Het is an imidazolinone group l~cking a CH2NR9Rl~ may be reacted with paraformaldehyde and an amine for example a secondary amine such as pyrrolidine to give a compound wherein the imidazolinone ring is substituted by CH2NR9R1~ where R9, R10 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom or a second nitrogen atom which will be part of a NH or NRC moiety, where Rc is as previously defined.
2s This reaction may be performed in a conventional manner, for instance, in a suitable solvent such as an alcohol, for example, methanol at an elevated temperature up to the boiling point of the solvent.
Intermediates of formula (II) may be prepared by reaction of a compound of formula (X[II) with a compound of formula (XIV):
CA 0221~700 1997-09-17 R4 Rs Rl HzN ~ ~ R RZ (XIV) (XIII) wherein R1, R2, R3, R4, R5, R7 and R3 are as defined in relation to formula (I) and LG is as previously defined. Preferably LG is a halogen atom, 5 expecially a bromine atom.
The reaction is effected in a conventional manner, for example in an organic solvent such as dimethylform~mide in the presence of a base such as, for example, an alkali metal hydride, such as sodium hydride.
Compounds of formula (XIII) may be prepared from known starting 0 materials by the reaction of a compound of formula (XV) with a compound of formula (~VI), followed by removal of the N-protecting group:
R4 Rs Rl ~ LG ~ R
HN ~ OH R8 R3 PG R
(XV) (XVI) 15 where LG is as previously defined and PG is a conventional amine protecting group, such as tert-butoxycarbonyl. The reaction is conveniently effected in a suitable organic solvent, such as dimethylformide in the presence of a base, such as, for example, an ~lkali metal hydride, such as sodium hydride. Removal of the protecting group CA 0221~700 1997-09-17 will depend upon the choice of protecting group. A tert-butoxycarbonyl group may be removed, for instance, using trifluoroacetic acid.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective C~roups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent 0 stage using methods known from the art.
The exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Spe-ific~t;on No.
WO 93/01165. The compounds were found to be active with IC50 at the NK1 receptor of less than 1~1M on said test method.
1S The following non-limiting Examples serve to illustrate the preparation of compounds of the present invention:
4-(N-((2-((3.5-Bis(trifluoromethyl)phenvl)methvloxy)- l-(S)-phenvl)ethyl-N-(2'-methoxvethvl))aminomethvl)-5-(N'.N'-dimethvlaminomethyl)- 1.2,3-triazole a) (2S)- 1-((3~5-Bis(trifluoromethvl)phenvl)methvloxv)-2-(2 methoxyethvlamino)-2 -phenvlethane L-2-Ammonium- 1-(3',5'-bis(trifluoromethyVphenyl)methyloxy-2-phenylethane (2g) was dissolved in (limethylform ~mi de (lOml). Sodium hydride (264mg, 60%) was added followed by 2-bromoethyl methyl ether (1.2g) and the mixture heated for 4 hours at 60~C. The reaction was quenched with water, extracted with ethyl acetate, washed with water (x2) and brine, dried (MgSO4) and evaporated i71 vacuo. The residue was purified on silica gel eluting with 10% ethyl acetate/petroleum ether (60-CA 0221~700 1997-09-17 W 096/Z9317 _34_ PCT/GB96/00586 80~C) to give the title compound. lH NMR (250MHz,CDCl3) ~ 2.09 (lH, vbr s), 2.59-2.75 (2H, m), 3.35 (3H, s), 3.42-3.50 (2H, m), 3.54-3.64 (2H, m), 3.97 (lH, m), 4.62 (2H, s), 7.25-7.41 (5H, m), 7.76 (2H, s), 7.79 (lH, s).
b) (2S)-1-((3.5-Bis(trifluoromethvl)Phenvl)methvloxy)-2-(N-(2'-methoxvethyl)-N-(4-chloro-2-butvne))amino-2 -phenvlethane The product from step (a) (0.6g) was dissolved in dimethylform~mi-l~ (6ml) and added dropwise to a pre-heated (60~C) solution of 1,4-dichloro-2-butyne (0.35g) and potassium carbonate (0.59g) o in dimethylformamide (6ml). The mixture was stirred for 4 hours and was then extracted with ethyl acetate and water. The organic layer was washed (H20, brine), dried (MgSO4) and evaporated in vacuo. The residue was purified on a gravity silica column using 10% ethyl acetate/petroleum ether (60-80~C) as eluant to give the title compound. lH NMR
(250MHz,CDC13) ~ 2.73 (2H, m), 3.23 (3H, s), 3.38 (2H, t, J=5.8Hz), 3.48 (lH, s), 3.56 (lH, s), 3.70-3.76 (lH, m), 3.81-3.91 (2H, m), 4.09 (2H, m), 7.19-7.29 (5H, m), 7.58 (2H, s), 7.68 (lH, s).
c) (2S)- 1-((3,5-Bis(trifluoromethvl)Phenvl)methvloxv)-2-(2'-methoxvethvl)-N-(4-azido-2-butvne)amino-2-Phenv] ethane -The product from step (b) (lOOmg) and sodium azide (16mg) were stirred together in dimethylsulfoxide under nitrogen for 16 hours. The reaction mixture was partitioned between ammonium chloride and ethyl acetate (4:1). The organic layer was washed (H2O, brine), dried (MgSO4) and evaporated in vacuo. The residue was purified on a gravity silica column using 20% ethyl acetate/ petroleum ether (60-80~C) as eluant to give the title compound. IH NMR (250MHz,CDCl3) ~ 2.72-2.81 (2H, m), 3.30 (3H, s), 3.41-3.48 (2H, m), 3.60 (lH, m), 3.62 (lH, br s), 3.75-4.00 (5H, m), 4.56 (2H, s), 7.26-7.40 (5H, m), 7.64 (2H, s), 7.75 (lH, s).
CA 0221~700 1997-09-17 d) 4-(N-((2-((3~5-Bis(trifluoromethvl)~henvl)methvloxv)- 1-(S)-phenvl)ethvl-N-(2'-methoxyethvl))aminomethvl)-5-(N',N'-dimethylaminomethvl)- 1.2,3-triazole The product from step (c) (lOOmg) and dimethylamine (0.5ml) in 1,4-dioxane (2ml) was heated with stirring in a sealed tube at 70~C for 5 hours. The reaction mixture was then cooled and evaporated in uacuo.
The residue was purified on a gravity silica column using 10%-20%
methanol/ethyl acetate as eluant to give the title compound. lH NMR
(250MHz,CDCl3) ~ 2.13 (6H, s), 2.~6-2.75 (lH, m), 2.82-2.92 (lH, m), 3.27 0 (3H, s), 3.37-3.44 (4H, m), 3.77-3.83 (2H, m), 3.88-3.9(~ (2H, m), 4.05 (lH, t, J=(~.29Hz), 4.54 (2H, s), 7.19-7.27 (5H, m), 7.G4 (2H, s), 7.72 (lH, s). MS
(ES) = 559.
Claims (26)
1. A compound of the formula (I):
(I) wherein R1 represents hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C1-6alkoxy, C1-4alkyl substituted by a hydroxy or C1-4alkoxy group, OCF3, hydroxy, trifluoromethyl, trimethylsilyl, nitro, CN, SRa, SORa, SO2Ra, CORa, CO2Ra or CONRaRb where Ra and Rb are each independently hydrogen or C1-4alkyl;
R2 and R3 each independently represent hydrogen, halogen, C1-6alkyl, C1-6alkoxy substituted by a C1-4alkoxy group, or trifluoromethyl;
R4 represents hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C1-6alkoxy, C1-4alkyl substituted by a hydroxy or C1-4alkoxy group, OCF3, hydroxy, trifluoromethyl, trimethylsilyl, nitro, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, CONRaRb where Ra and Rb are as previously defined;
R5 represents hydrogen, halogen, C1-6alkyl, C1-6alkoxy substituted by a C1-4alkoxy group, or trifluoromethyl;
R6, R7 and R8 each independently represent hydrogen or a C1-4alkyl group optionally substituted by a hydroxy group;
Het represents a 5- or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =O, =S or a C1-4alkyl group, and optionally substituted by a group of the formula ZNR9R10 where Z is C1-6alkylene or C3-6cycloalkyl;
R9 is hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxyl;
R10 is hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by C1-4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R9, R10 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy or C1-4alkoxy optionally substituted by a C1-4alkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH
or NRc moiety where Rc is C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy;
or R9, R10 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or Z, R9 and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
or a pharmaceutically acceptable salt thereof.
(I) wherein R1 represents hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C1-6alkoxy, C1-4alkyl substituted by a hydroxy or C1-4alkoxy group, OCF3, hydroxy, trifluoromethyl, trimethylsilyl, nitro, CN, SRa, SORa, SO2Ra, CORa, CO2Ra or CONRaRb where Ra and Rb are each independently hydrogen or C1-4alkyl;
R2 and R3 each independently represent hydrogen, halogen, C1-6alkyl, C1-6alkoxy substituted by a C1-4alkoxy group, or trifluoromethyl;
R4 represents hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C1-6alkoxy, C1-4alkyl substituted by a hydroxy or C1-4alkoxy group, OCF3, hydroxy, trifluoromethyl, trimethylsilyl, nitro, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, CONRaRb where Ra and Rb are as previously defined;
R5 represents hydrogen, halogen, C1-6alkyl, C1-6alkoxy substituted by a C1-4alkoxy group, or trifluoromethyl;
R6, R7 and R8 each independently represent hydrogen or a C1-4alkyl group optionally substituted by a hydroxy group;
Het represents a 5- or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =O, =S or a C1-4alkyl group, and optionally substituted by a group of the formula ZNR9R10 where Z is C1-6alkylene or C3-6cycloalkyl;
R9 is hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxyl;
R10 is hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by C1-4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R9, R10 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy or C1-4alkoxy optionally substituted by a C1-4alkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH
or NRc moiety where Rc is C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy;
or R9, R10 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or Z, R9 and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim 1 wherein R1 is hydrogen, C1-4alkyl, C1-4alkoxy, halogen or CF3.
3. A compound as claimed in claim 1 or claim 2 wherein R2 is hydrogen, C1-4alkyl, C1-4alkoxy, halogen or CF3.
4. A compound as claimed in any one of claims 1 to 3 wherein R3 is hydrogen, fluorine, chlorine or CF3.
5. A compound as claimed in any one of claims 1 to 4 wherein R1 and R2 are in the 3 and 5 positions of the phenyl ring.
6. A compound as claimed in any one of claims 1 to 5 wherein R4 is hydrogen and R5 is hydrogen or 4-fluoro.
7. A compound as claimed in any one of claims 1 to 6 wherein R6 and R7 are each independently hydrogen or methyl.
8. A compound as claimed in any one of claims 1 to 7 wherein R8 is hydrogen or C1-2alkyl optionally substituted by a hydroxy group.
9. A compound as claimed in any one of claims 1 to 8 wherein Het represents a heterocyclic ring selected from:
; ; ;
; ; ;
; ; and .
; ; ;
; ; ;
; ; and .
10. A compound as claimed in claim 9 wherein Het is:
.
.
11. A compound as claimed in any one of claims 1 to 10 wherein Z is CH2 or CH2CH2 and NR9R10 is amino, methylamino, dimethylamino, diethylamino, azetidinyl, pyrrolidino and morpholino.
12. A compound of the formula (Ia):
(Ia) wherein R8 and Het are as defined in claim 1 and A1 is fluorine or CF3;
A2 is fluorine or CF3; and A3 is hydrogen or fluorine;
or a pharmaceutically acceptable salt thereof.
(Ia) wherein R8 and Het are as defined in claim 1 and A1 is fluorine or CF3;
A2 is fluorine or CF3; and A3 is hydrogen or fluorine;
or a pharmaceutically acceptable salt thereof.
13. The compound:
4-(N-((2-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-1-(S)-phenyl)ethyl-N-(2'-methoxyethyl))aminomethyl)-5-(N',N'-dimethylaminomethyl)-1,2,3-triazole;
or a pharmaceutically acceptable salt thereof.
4-(N-((2-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-1-(S)-phenyl)ethyl-N-(2'-methoxyethyl))aminomethyl)-5-(N',N'-dimethylaminomethyl)-1,2,3-triazole;
or a pharmaceutically acceptable salt thereof.
14. A process for the preparation of a compound as claimed in any one of claims 1 to 13, which comprises (A) reacting a compound of formula (II) (II) wherein R1, R2, R3, R4, R5, R6, R7 and R3 are as defined in claim 1 with a compound of formula (III):
LG-CH2-Het' (III) where Het' is a group of the formula Het as defined in claim 1 or a precursor therefor and LG is a leaving group such as an alkyl- or arylsulphonyloxy group or a halogen atom; and, if Het' is a precursor group, converting it to a group Het; or (B), where Het represents 1,2,3-triazol-4-yl substituted by CH2NR9R10, by reaction of a compound of formula (V) (V) with an azide, followed by reduction of the carbonyl group adjacent to -NR9R10 using a suitable reducing agent; or (C), where Het represents 1,2,3-triazol-4-yl substituted by CH2NR9R10, by reaction of a compound of formula (VI) (VI) with an amine of formula NHR9R10; or (D), where Het represents substituted or unsubstituted 1,3,5-triazine by reaction of intermediates of formula (VII):
(VII) with substituted or unsubstituted 1,3,5-triazine; or (E), where Het represents substituted or unsubstituted 1,2,4-triazine by reaction of an intermediate of formula (VIII) with a dicarbonyl compound of formula (IX):
(VIII) (IX) wherein R35 represents H or ZNR9R10; or (F), where Het represents a substituted 1,2,4-triazolyl group by reaction of an intermediate of formula (II) with a compound of formula (X) (X) wherein Hal is a halogen atom, and R18 is H, CONH2 or OCH3, (which is converted to an oxo substituent under the reaction conditions), in the presence of a base, followed where necessary by conversion to a compound of formula (I); or (G), where Het represents thioxotriazolyl from intermediates of formula (XI) (XI) by reaction with a compound of formula HNCS, in the presence of a base;
each process being followed, where necessary, by the removal of any protecting group where present;
and when the compound of formula (I) is obtained as a mixture of enantiomers or diastereoisomers, optionally resolving the mixture to obtain the desired enantiomer;
and/or, if desired, converting the resulting compound of formula (I) or a salt thereof, into a pharmaceutically acceptable salt thereof.
LG-CH2-Het' (III) where Het' is a group of the formula Het as defined in claim 1 or a precursor therefor and LG is a leaving group such as an alkyl- or arylsulphonyloxy group or a halogen atom; and, if Het' is a precursor group, converting it to a group Het; or (B), where Het represents 1,2,3-triazol-4-yl substituted by CH2NR9R10, by reaction of a compound of formula (V) (V) with an azide, followed by reduction of the carbonyl group adjacent to -NR9R10 using a suitable reducing agent; or (C), where Het represents 1,2,3-triazol-4-yl substituted by CH2NR9R10, by reaction of a compound of formula (VI) (VI) with an amine of formula NHR9R10; or (D), where Het represents substituted or unsubstituted 1,3,5-triazine by reaction of intermediates of formula (VII):
(VII) with substituted or unsubstituted 1,3,5-triazine; or (E), where Het represents substituted or unsubstituted 1,2,4-triazine by reaction of an intermediate of formula (VIII) with a dicarbonyl compound of formula (IX):
(VIII) (IX) wherein R35 represents H or ZNR9R10; or (F), where Het represents a substituted 1,2,4-triazolyl group by reaction of an intermediate of formula (II) with a compound of formula (X) (X) wherein Hal is a halogen atom, and R18 is H, CONH2 or OCH3, (which is converted to an oxo substituent under the reaction conditions), in the presence of a base, followed where necessary by conversion to a compound of formula (I); or (G), where Het represents thioxotriazolyl from intermediates of formula (XI) (XI) by reaction with a compound of formula HNCS, in the presence of a base;
each process being followed, where necessary, by the removal of any protecting group where present;
and when the compound of formula (I) is obtained as a mixture of enantiomers or diastereoisomers, optionally resolving the mixture to obtain the desired enantiomer;
and/or, if desired, converting the resulting compound of formula (I) or a salt thereof, into a pharmaceutically acceptable salt thereof.
15. A compound as claimed in any one of claims 1 to 13 for use in therapy.
16. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 13 in association with a pharmaceutically acceptable carrier or excipient.
17. A method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof.
18. A method according to claim 17 for the treatment or prevention of pain or inflammation.
19. A method according to claim 17 for the treatment or prevention of migraine.
20. A method according to claim 17 for the treatment or prevention of emesis.
21. A method according to claim 17 for the treatment or prevention of postherpetic neuralgia.
22. The use of a compound as claimed in any one of claims 1 to 13 for the manufacture of a medicament for the treatment or prevention of a physiological disorder associated with an excess of tachykinins.
23. The use of a compound as claimed in any one of claims 1 to 13 for the manufacture of a medicament for the treatment or prevention of pain or inflammation.
24. The use of a compound as claimed in any one of claims 1 to 13 for the manufacture of a medicament for the treatment or prevention of migraine.
25. The use of a compound as claimed in any one of claims 1 to 13 for the manufacture of a medicament for the treatment or prevention of emesis.
26. The use of a compound as claimed in any one of claims 1 to 13 for the manufacture of a medicament for the treatment or prevention of postherpetic neuralgia.
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GB9505492.0 | 1995-03-18 | ||
GBGB9505492.0A GB9505492D0 (en) | 1995-03-18 | 1995-03-18 | Therapeutic agents |
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CA2215700A1 true CA2215700A1 (en) | 1996-09-26 |
Family
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CA002215700A Abandoned CA2215700A1 (en) | 1995-03-18 | 1996-03-13 | Aromatic compounds useful as tachykinin antagonists |
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US (1) | US5962485A (en) |
EP (1) | EP0815088A1 (en) |
JP (1) | JPH11502220A (en) |
AU (1) | AU5009796A (en) |
CA (1) | CA2215700A1 (en) |
GB (1) | GB9505492D0 (en) |
WO (1) | WO1996029317A1 (en) |
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AU2898297A (en) * | 1996-05-24 | 1998-01-05 | Novartis Ag | Use of substance p antagonists for treating social phobia |
NZ523310A (en) * | 2000-06-12 | 2005-07-29 | Univ Rochester | Tachykinin receptor antagonist to block receptors NK1, NK2, and NK3 and treat symptoms of hormonal variation |
PT1675846E (en) * | 2003-10-24 | 2010-04-20 | Lilly Co Eli | Novel crystalline forms of {2-[1-(3,5-bis-trifluoromethylbenzyl)-5-pyridin-4-yl-1h- [1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone |
KR101412339B1 (en) | 2004-07-15 | 2014-06-25 | 알바니 몰레큘라 리써치, 인크. | Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
US8362075B2 (en) | 2005-05-17 | 2013-01-29 | Merck Sharp & Dohme Corp. | Cyclohexyl sulphones for treatment of cancer |
US7956050B2 (en) | 2005-07-15 | 2011-06-07 | Albany Molecular Research, Inc. | Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
EP1940842B1 (en) | 2005-09-29 | 2012-05-30 | Merck Sharp & Dohme Corp. | Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators |
GB0603041D0 (en) | 2006-02-15 | 2006-03-29 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
WO2008039327A2 (en) | 2006-09-22 | 2008-04-03 | Merck & Co., Inc. | Method of treatment using fatty acid synthesis inhibitors |
US20110218176A1 (en) | 2006-11-01 | 2011-09-08 | Barbara Brooke Jennings-Spring | Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development |
PL2336120T3 (en) | 2007-01-10 | 2014-12-31 | Msd Italia Srl | Combinations containing amide substituted indazoles as poly(adp-ribose)polymerase (parp) inhibitors |
US8106086B2 (en) | 2007-04-02 | 2012-01-31 | Msd K.K. | Indoledione derivative |
CA2690191C (en) | 2007-06-27 | 2015-07-28 | Merck Sharp & Dohme Corp. | 4-carboxybenzylamino derivatives as histone deacetylase inhibitors |
WO2009111354A2 (en) | 2008-03-03 | 2009-09-11 | Tiger Pharmatech | Tyrosine kinase inhibitors |
US9156812B2 (en) | 2008-06-04 | 2015-10-13 | Bristol-Myers Squibb Company | Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine |
WO2010114780A1 (en) | 2009-04-01 | 2010-10-07 | Merck Sharp & Dohme Corp. | Inhibitors of akt activity |
WO2010132487A1 (en) | 2009-05-12 | 2010-11-18 | Bristol-Myers Squibb Company | CRYSTALLINE FORMS OF (S)-7-([1,2,4]TRIAZOLO[1,5-a]PYRIDIN-6-YL)-4-(3,4-DICHLOROHPHENYL)-1,2,3,4-TETRAHYDROISOQUINOLINE AND USE THEREOF |
KR101830447B1 (en) | 2009-05-12 | 2018-02-20 | 알바니 몰레큘라 리써치, 인크. | 7-([1,2,4]TRIAZOLO[1,5-α]PYRIDIN-6-YL)-4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDROISOQUINOLINE AND USE THEREOF |
US9034899B2 (en) | 2009-05-12 | 2015-05-19 | Albany Molecular Research, Inc. | Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof |
PE20121172A1 (en) | 2009-10-14 | 2012-09-05 | Merck Sharp & Dohme | PIPERIDINS SUBSTITUTED WITH ACTIVITY IN HDM2 |
US8999957B2 (en) | 2010-06-24 | 2015-04-07 | Merck Sharp & Dohme Corp. | Heterocyclic compounds as ERK inhibitors |
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US9351965B2 (en) | 2010-12-21 | 2016-05-31 | Merck Sharp & Dohme Corp. | Indazole derivatives useful as ERK inhibitors |
IN2013MN02170A (en) | 2011-04-21 | 2015-06-12 | Piramal Entpr Ltd | |
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EP2844261B1 (en) | 2012-05-02 | 2018-10-17 | Sirna Therapeutics, Inc. | SHORT INTERFERING NUCLEIC ACID (siNA) COMPOSITIONS |
WO2014052563A2 (en) | 2012-09-28 | 2014-04-03 | Merck Sharp & Dohme Corp. | Novel compounds that are erk inhibitors |
MX363243B (en) | 2012-11-28 | 2019-03-14 | Merck Sharp & Dohme | Compositions and methods for treating cancer. |
BR112015013611A2 (en) | 2012-12-20 | 2017-11-14 | Merck Sharp & Dohme | compound and pharmaceutical composition |
EP2951180B1 (en) | 2013-01-30 | 2018-05-02 | Merck Sharp & Dohme Corp. | 2,6,7,8 substituted purines as hdm2 inhibitors |
EP3041938A1 (en) | 2013-09-03 | 2016-07-13 | Moderna Therapeutics, Inc. | Circular polynucleotides |
WO2019094311A1 (en) | 2017-11-08 | 2019-05-16 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
WO2020033284A1 (en) | 2018-08-07 | 2020-02-13 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
US20210277009A1 (en) | 2018-08-07 | 2021-09-09 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
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CA2099233A1 (en) * | 1992-06-29 | 1993-12-30 | Conrad P. Dorn | Morpholine and thiomorpholine tachykinin receptor antagonists |
-
1995
- 1995-03-18 GB GBGB9505492.0A patent/GB9505492D0/en active Pending
-
1996
- 1996-03-13 CA CA002215700A patent/CA2215700A1/en not_active Abandoned
- 1996-03-13 US US08/913,567 patent/US5962485A/en not_active Expired - Fee Related
- 1996-03-13 WO PCT/GB1996/000586 patent/WO1996029317A1/en not_active Application Discontinuation
- 1996-03-13 EP EP96906838A patent/EP0815088A1/en not_active Withdrawn
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WO1996029317A1 (en) | 1996-09-26 |
US5962485A (en) | 1999-10-05 |
AU5009796A (en) | 1996-10-08 |
EP0815088A1 (en) | 1998-01-07 |
JPH11502220A (en) | 1999-02-23 |
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